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Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro
Abstract
We have recently shown that the anticonvulsant drugs phenytoin, lamotrigine and sodium valproate all reduce the release of glutamate at synapses in the entorhinal cortex in vitro. In the present investigation we determined whether this property was shared by gabapentin and pregabalin, using whole-cell patch-clamp recordings of excitatory postsynaptic currents (EPSCs) in layer V neurons in slices of rat entorhinal cortex. Both drugs reduced the amplitude and increased the paired-pulse ratio of EPSCs evoked by electrical stimulation of afferent inputs, suggesting a presynaptic effect to reduce glutamate release. The frequency of spontaneous EPSCs (sEPSCs) was concurrently reduced by GBP, further supporting a presynaptic action. There was no significant change in amplitude although a slight reduction was seen, particularly with gabapentin, which may reflect a reduction in the number of larger amplitude sEPSCs. When activity-independent miniature EPSCs were recorded in the presence of tetrodotoxin, both drugs continued to reduce the frequency of events with no change in amplitude. The reduction in frequency induced by gabapentin or pregabalin was blocked by application of the l-amino acid transporter substrate l-isoleucine. The results show that gabapentin and pregabalin, like other anticonvulsants, reduce glutamate release at cortical synapses. It is possible that this reduction is a combination of two effects: a reduction of activity-dependent release possibly via interaction with P/Q-type voltage-gated Ca channels, and a second action, as yet unidentified, occurring downstream of Ca influx into the presynaptic terminals.
... Considerable electrophysiological studies have shown that GBPs reduce glutamate and glycine release from presynaptic nerve terminals [79,80] by interacting with P/Qtype calcium channels [79,81]. In addition, spectroscopy research has suggested that healthy rat forebrain glutamate concentrations decreased by 7%, 2 h after injecting 100 mg/ kg of gabapentin and by 4% after injecting 1000 mg/kg of gabapentin [80]. ...
... Considerable electrophysiological studies have shown that GBPs reduce glutamate and glycine release from presynaptic nerve terminals [79,80] by interacting with P/Qtype calcium channels [79,81]. In addition, spectroscopy research has suggested that healthy rat forebrain glutamate concentrations decreased by 7%, 2 h after injecting 100 mg/ kg of gabapentin and by 4% after injecting 1000 mg/kg of gabapentin [80]. ...
... Cunningham et al. [79] used rat entorhinal synapses with whole-cell patch-clamp recordings. They reported that pregabalin and gabapentin reduced the amplitude and frequency of EPSCs and increased the paired-pulse ratio of EPSCs induced by electrical stimulation of afferent inputs. ...
Background
Current approaches for managing benzodiazepine (BZD) withdrawal symptoms are daunting for clinicians and patients, warranting novel treatment and management strategies. This review discusses the pharmacodynamic properties of BZDs, gabapentinoids (GBPs), endozepines, and novel GABAergic compounds associated with potential clinical benefits for BZD-dependent patients. The objective of this study was to review the complex neuromolecular changes occurring within the GABAergic and glutamatergic systems during the BZD tolerance and withdrawal periods while also examining the mechanism by which GBPs and alternative pharmacological therapies may attenuate withdrawal symptoms.Methods and ResultsAn elaborative literature review was conducted using multiple platforms, including the National Center for Biotechnology (NCBI), AccessMedicine, ScienceDirect, pharmacology textbooks, clinical trial data, case reports, and PubChem. Our literature analysis revealed that many distinctive neuroadaptive mechanisms are involved in the GABAergic and glutamatergic systems during BZD tolerance and withdrawal. Based on this data, we hypothesize that GBPs may attenuate the overactive glutamatergic system during the withdrawal phase by an indirect presynaptic glutamatergic mechanism dependent on the α2δ1 subunit expression.ConclusionsGBPs may benefit individuals undergoing BZD withdrawal, given that the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor current significantly increases during abrupt BZD withdrawal in animal studies. This may be a conceivable explanation for the effectiveness of GBPs in treating both alcohol withdrawal symptoms and BZD withdrawal symptoms in some recent studies. Finally, natural and synthetic GABAergic compounds with unique pharmacodynamic properties were found to exert potential clinical benefits as BZD substitutes in animal studies, though human studies are lacking.
... Mirogabalin has selective and potent binding affinities for human α2δ subunits of VGCCs, which reduce calcium (Ca 2+ ) influx and neurotransmission in DRG, inhibiting neurotransmitter release in presynaptic neuron endings [8]. Following inhibited neurotransmitter release (e.g., calcitonin gene-related peptide (CGRP), glutamate, substance P), the hyperexcitability of central nervous system (CNS) neurons decreases, which has a number of pharmacological effects, including analgesic, anxiolytic, and anticonvulsant ones [9]. Four α2δ subunits of VGCCs have been recognized; the α2δ-1 subunit is mainly present in neuronal cells, but the other subunits, α2δ-2, α2δ-3, and α2δ-4, are also present in non-neuronal cells [10]. ...
... This applied mainly to the α2δ-1 subunit of VGCCs: the dissociation half-life from the α2δ-1 subunit is 11.1 h, and from the α2δ-2 subunit, it is 2.4 h for mirogabalin vs. 1.4 h from both α2δ-1 and α2δ-2 subunits for pregabalin [19]. These differences explain the diverse efficacy and safety profiles of mirogabalin compared to other gabapentinoids because the α2δ-1 subunits of VGCCs have been linked with gabapentinoids analgesic properties [9], whereas the α2δ-2 subunits of VGCCs with the adverse CNS effects [22]. According to experimental data, mirogabalin's safety profile is superior to pregabalin's, which is evidenced by the comparison of dosages that produce 50% of the maximum adverse effect and 50% of maximum analgesia, respectively [19]. ...
... It was shown, that after administration mirogabalin is quickly converted into its free form in which A200-700 is the main active circulating isoform [24]. The main cytochrome P450 isoenzymes are not induced or inhibited by mirogabalin [9]. The drug is cleared mainly unchanged (61-72%) via renal excretion by filtration and active secretion, however a slight fraction (13-20%) is metabolized by hepatic uridine 5′-diphospho-glucuronosyltransferase isoforms [24]. ...
The efficacy of neuropathic pain control remains unsatisfactory. Despite the availability of a variety of therapies, a significant proportion of patients suffer from poorly controlled pain of this kind. Consequently, new drugs and treatments are still being sought to remedy the situation. One such new drug is mirogabalin, a selective ligand for the α2δ subunits of voltage-gated calcium channels (VGCC) developed by Sankyo group for the management of neuropathic pain. In 2019 in Japan, mirogabalin was approved for peripheral neuropathic pain following the encouraging results of clinical trials conducted with diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN) patients. The ligand selectivity of mirogabalin for α2δ-1 and α2δ-2 and its slower dissociation rate for α2δ-1 than for α2δ-2 subunits of VGCC may contribute to its strong analgesic effects, wide safety margin, and relatively lower incidence of adverse effects compared to pregabalin and gabapentin. This article discusses the mechanism of action of mirogabalin, presents data on its pharmacodynamics and pharmacokinetics, and reviews the available experimental and clinical studies that have assessed the efficacy and safety of the drug in the treatment of selected neuropathic pain syndromes.
... Furthermore, gabapentin affects the regulation of neurotransmitter release, preventing the release of neurotransmitters such as glutamate (Bonnet et al., 1999;Coderre et al., 2007;Prisciandaro et al., 2021). In a rat model, gabapentin led to the inhibition of K + -triggered glutamate release in the neocortical and hippocampal brain area (Dooley et al., 2000;Cunningham et al., 2004). Gabapentin is also effective in treating somatic symptoms during alcohol withdrawal (Voris et al., 2003;Mariani et al., 2006), as well as in reducing withdrawal-induced CNS hyperexcitability (Watson et al., 1997). ...
... Rimonabant (SR141716) is a selective CB1 receptor blocker effective in the treatment of obesity, tobacco smoking and cardiometabolic risk factors such as hyperlipidaemia and hyperglycaemia in diabetes (Curioni and André, 2006;Gelfand and Cannon, 2006). ...
Compounds known to be successful in the treatment of alcohol use disorder include the aversive agent, Disulfiram, the glutamatergic NMDA receptor antagonist, Acamprosate, and the opioid receptor antagonists, Naltrexone and Nalmefene. Although all four are effective in maintaining abstinence or reduction of alcohol consumption, only a small percentage of patients receive pharmacological treatment. In addition, many other medications have been investigated for their therapeutic potential in the treatment of alcohol use disorder. In this review we summarize and compare Baclofen, Gabapentin, Topiramate, Ondansetron, Varenicline, Aripiprazole, Quetiapine, Clozapine, Antidepressants, Lithium, Neuropeptide Y, Neuropeptide S, Corticotropin-releasing factor antagonists, Oxytocin, PF-05190457, Memantine, Ifenprodil, Samidorphan, Ondelopran, ABT-436, SSR149415, Mifepristone, Ibudilast, Citicoline, Rimonabant, Surinabant, AM4113 and Gamma-hydroxybutyrate While some have shown promising results in the treatment of alcohol use disorder, others have disappointed and should be excluded from further investigation. Here we discuss the most promising results and highlight medications that deserve further preclinical or clinical study. Effective, patient-tailored treatment will require greater understanding provided by many more preclinical and clinical studies.
... A spinal site of action is also possible because of high opioid receptor expression in the superficial dorsal horn. A dual mode of action is suggested for tapentadol: agonism at the MOR and inhibition of the synaptosomal reuptake of noradrenaline [55,56]. Additional data on tapentadol relevant for pharmacometric evaluation are provided in Table 2, and a simulated PK profile is provided in Figure 4. ...
... Nevertheless, lacosamide, pregabalin and tapentadol may be expected to differ in the relative size of their effects on nociceptive processing at the peripheral, spinal and supraspinal levels, leading to differential effects on the biomarkers derived from neuronal activity at these levels. Moreover, lacosamide, pregabalin and tapentadol differ in their modes of action [25,[45][46][47][48][49][50][51][52]56]. ...
There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets and actions on compartments of the nociceptive system are missing in both rodents and humans. Through the Innovative Medicines Initiative of the European Union and EFPIA, a consortium of researchers from academia and the pharmaceutical industry was established to identify and validate a set of functional biomarkers to assess drug-induced effects on nociceptive processing at peripheral, spinal and supraspinal levels using electrophysiological and functional neuroimaging techniques. Here, we report the results of a systematic literature search for pharmacological probes that allow for validation of these biomarkers. Of 26 candidate substances, only 7 met the inclusion criteria: evidence for nociceptive system modulation, tolerability, availability in oral form for human use and absence of active metabolites. Based on pharmacokinetic characteristics, three were selected for a set of crossover studies in rodents and healthy humans. All currently available probes act on more than one compartment of the nociceptive system. Once validated, biomarkers of nociceptive signal processing, combined with a pharmacometric modelling, will enable a more rational approach to selecting dose ranges and verifying target engagement. Combined with advances in classification of chronic pain conditions, these biomarkers are expected to accelerate analgesic drug development.
... In each of these studies, the drugs gabapentin or pregabalin normalize pathologically elevated rates of mEPSCs in rat or mouse neuronal tissue with synapses in spinal cord dorsal horn (Patel et al., 2000;Li et al., 2014b;Matsuzawa et al., 2014;Zhou and Luo, 2014;Zhou and Luo, 2015;Park et al., 2016;Alles et al., 2017;Chen et al., 2018;Chen et al., 2019;Deng et al., 2019). Gabapentinoids reduced the rate of mEPSCs between glutamatergic neurons in rat entorhinal cortex (Cunningham et al., 2004), in neocortex neurons after cortical freeze lesions (Andresen et al., 2014;Lau et al., 2017), between neocortex and striatal neurons , at glutamate neurons in hypothalamus of spontaneously hypertensive rats , at the mouse calyx of Held (Di Guilmi et al., 2011) and in cortico-striatal synapses after prolonged prior stimulation of striatum (Nagai et al., 2019). Therefore, the most widely replicated effects of gabapentin and pregabalin at the cellular level are decreases in the rate of mEPSCs at excitatory synapses, particularly at synapses with pathologically enhanced activity. ...
... It was previously shown that cortico-striatal LTP requires presynaptic NMDA receptors (Park et al., 2014) and it has become clear that presynaptic NMDA receptors have different properties from the more widely-studied postsynaptic NMDA receptors of neocortical and hippocampal neurons (Banerjee et al., 2016;Dore et al., 2017;Bouvier et al., 2018). Other findings suggest that gabapentin may reduce presynaptic NMDA receptor activity in area CA1 of rat hippocampal slices (Suarez et al., 2005) and in entorhinal cortex slices, where gabapentin reduced the occurrence of spontaneous miniature synaptic events (Cunningham et al., 2004). ...
The gabapentinoid drugs gabapentin and pregabalin (Neurontin® and Lyrica®) are mainstay treatments for neuropathic pain and for preventing focal seizures. Both drugs have similar effects to each other in animal models and clinically. Studies have shown that a protein first identified as an auxiliary subunit of voltage-gated calcium channels (the alpha2-delta subunit, a2d-1 or CaVa2d1) is the high-affinity binding site for gabapentin and pregabalin, and is required for the efficacy of these drugs. The a2d-1 protein is required for the ability of gabapentin and pregabalin to reduce neurotransmitter release in neuronal tissue, consistent with a therapeutic mechanism of action via voltage-gated calcium channels. However, recent studies have revealed that a2d-1 interacts with several proteins in addition to voltage-gated calcium channels, and these additional proteins could be involved in gabapentinoid pharmacology. Furthermore, gabapentin and pregabalin have been shown to modify the action of a subset of NMDA-sensitive glutamate receptors, neurexin-1a, and thrombospondin proteins by binding to a2d-1. Thus, these effects may contribute substantially to gabapentinoid therapeutic mechanism of action.
... Gabapentinoid therapy results in reduced frequency of excitatory postsynaptic currents and mitigates the postsynaptic release of glutamate, norepinephrine and substance P (44)(45)(46)(47) . VGCCs, namely the α 2 δ-1, α 2 δ-2, α 2 δ-3 and α 2 δ-4 subunits (48), are the target sites of gabapentinoid therapy (49) . ...
... Mirogabalin is a potent, selective ligand of the α 2 δ-1 subunit which reduces calcium (Ca 2+ ) influx and ectopic neurotransmission in the DRG, thereby reducing the frequency of excitatory postsynaptic currents (44) . While there is a lack of data that directly indicate mirogabalin crossing the blood-brain barrier, other gabapentinoids enter the CNS through carriermediated transport (52) . ...
... Gabapentinoid therapy results in reduced frequency of excitatory postsynaptic currents and mitigates the postsynaptic release of glutamate, norepinephrine and substance P (44)(45)(46)(47). VGCCs, namely the α 2 δ-1, α 2 δ-2, α 2 δ-3 and α 2 δ-4 subunits (48), are the target sites of gabapentinoid therapy (49). ...
... Mirogabalin is a potent, selective ligand of the α 2 δ-1 subunit which reduces calcium (Ca 2+ ) influx and ectopic neurotransmission in the DRG, thereby reducing the frequency of excitatory postsynaptic currents (44). While there is a lack of data that directly indicate mirogabalin crossing the blood-brain barrier, other gabapentinoids enter the CNS through carriermediated transport (52). ...
Neuropathic pain (NeP) is a global cause of suffering and debilitation leading to significant morbidity and reduced quality of life. New treatments are needed to address the growing prevalence of NeP and its impact on sleep, mood and functionality. Mirogabalin besylate (mirogabalin, Tarlige) is a gabapentinoid therapy developed by Daiichi Sankyo which is approved in Japan for the treatment of postherpetic neuralgia and painful diabetic peripheral neuropathy. Mirogabalin has a potent pain-modulating effect with a unique high affinity and prolonged dissociation rate for the a2delta-1 subunit of voltage-gated calcium (Ca2+) channels (VGCCs) on the dorsal root ganglion resulting in more sustained analgesia compared with traditional gabapentinoids. Additionally, mirogabalin has a superior adverse events (AEs) profile due to a rapid dissociation from the a2delta-2 subunit of VGCCs potentially implicated in central nervous system-specific AEs. The most common AEs for mirogabalin are dizziness (approximately 8-16%), somnolence (approximately 6-24%) and headache (approximately 6-14%), with a lower incidence of constipation, nausea, diarrhea, vomiting, edema, fatigue and weight gain. Postmarketing studies are required to evaluate its analgesic durability and efficacy when combined with other antineuropathic agents such as tricyclics, duloxetine and tramadol/tapentadol.
... All medium poured and glutamate 10-5 mM for inducing toxicity were added to each wells except negative controls. After 10 min Pregabalin (5, 10 and 20 µgr) [21], Diazepam (1, 5 and 15 µgr) [22], Glucose (5, 10 and 15 µgr) [23] and combination group (P; Pregabalin, D; Diazepam and G; Glucose) were added to each well excepts negative control (NC) groups and incubated for 24 h (5% CO2; 37°C). Negative control, received 150 μL of NBM and positive control contained only 10-5 mM glutamate for 24 h [24]. ...
... Cunningham MO et al in their studies evaluate Pregabalin and gabapentin effect on glutamate release in entorhinal cortex synapse (21). In this study showed pregabalin reduced glutamate release at cortical synapses. ...
In this study we used pregabalin, diazepam and glucose for evaluating which one are more effective agents against glutamate induced neurotoxicity. After cortex culture preparation glutamate toxicity induced by adding 10-5 mM glutamate to each wells except negative control group. After 10 min different dose of diazepam, pregabalin and glucose were added for 24 h and then 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Total Antioxidant Status (TAC) and Total oxidant status (TOS) assays were done. Diazepam, dose dependently shows neuroprotective effects and low dose of diazepam did not increase cell viability higher than 80 %. Combination groups only in high dose increased neurons viability. Total Antioxidant capacity of Pregabalin also show correlation with diazepam groups and highest dose of both show nearest value to negative control group. In addition, lowest and highest oxidant level were gained by the negative and positive control groups respectively. Except high dose of combination group, all groups show statically difference in compare with the negative control group P [Med-Science 2018; 7(4.000): 797-801]
... peptydu związanego z genem kalcytoniny (CGRP), glutaminianu, substancji P) w szczelinie synaptycznej powoduje zmniejszenie pobudliwości neuronów znajdujących się w ośrodkowym układzie nerwowym [3]. Mechanizm ten odpowiada za działanie przeciwbólowe, przeciwdrgawkowe i anksjolityczne gabapentynoidów [4]. Do tej pory poznano 4 podjednostki α2δ napięciozależnych kanałów wapniowych (VGCCs). ...
Introduction: Mirogabalin is a new drug from the gabapentinoid group first registered in Japan in 2019. It has found use in the treatment of peripheral neuropathic pain in diabetic neuropathy and postherpetic neuropathy.
Purpose: In this article, we review studies on the efficacy and safety of mirogabalin in the treatment of registered indications and its potentially new applications.
Materials and Methods: We reviewed the literature available in the PubMed database, using the key words: "mirogabalin", "neuropathy" "pregabalin".
Results: Mirogabalin has been registered for the treatment of neuropathic pain in diabetic neuropathy and postherpetic neuropathy. The literature shows that it is effective and safe in the above-mentioned indications. Its use has also been described: in the treatment of neuropathic pain of other etiologies with intolerance to pregabalin, as a coanalgesic in the treatment of pain in the course of cancer, and in neuropathy caused by chemotherapy. It has been shown to be effective in all of the aforementioned cases. Studies have shown no clinically significant effect of mirogabalin in the symptomatic treatment of fibromyalgia pain. It has a good safety profile and a low number of adverse effects.
Conclusions:. Mirogabalin is a drug that has the potential to improve the efficacy of treatment of neuropathic pain due to various causes. There is a need to continue conducting studies on larger groups of patients in order to make wider use of its potential in clinical practice.
... Intracellular trafficking of Ca v is attenuated by α 2 δ ligands, such as gabapentin or pregabalin [8,9]. Together, these presynaptic effects may lead to an attenuated release of excitatory neurotransmitters, such as glutamate [10][11][12], and are one possible explanation for the anti-nociceptive properties of gabapentinoids. ...
Introduction:
Gabapentin and pregabalin are drugs to treat neuropathic pain. Several studies highlighted effects on presynaptic terminals of nociceptors. Via binding to α2δ subunits of voltage-gated calcium channels, gabapentinoids modulate the synaptic transmission of nociceptive information. However, recent studies revealed further properties of these substances. Treatment with gabapentin or pregabalin in animal models of neuropathic pain resulted not only in reduced symptoms of hyperalgesia but also in an attenuated activation of glial cells and decreased production of pro-inflammatory mediators in the spinal dorsal horn.
Methods:
In the present study, we aimed to investigate the impact of gabapentinoids on the inflammatory response of spinal dorsal horn cells, applying the established model of neuro-glial primary cell cultures of the superficial dorsal horn (SDH). We studied effects of gabapentin and pregabalin on lipopolysaccharide (LPS)-induced cytokine release (bioassays), expression of inflammatory marker genes (RT-qPCR), activation of transcription factors (immunocytochemistry), and Ca2+ responses of SDH neurons to stimulation with substance P and glutamate (Ca2+-imaging).
Results:
We detected an attenuated LPS-induced expression and release of interleukin-6 by SDH cultures in the presence of gabapentinoids. In addition, a significant main effect of drug treatment was observed for mRNA expression of microsomal prostaglandin E synthase 1 and the inhibitor of nuclear factor kappa B. Nuclear translocation of inflammatory transcription factors in glial cells was not significantly affected by gabapentinoid treatment. Moreover, both substances did not modulate neuronal responses upon stimulation with substance P or glutamate.
Conclusion:
Our results provide evidence for anti-inflammatory capacities of gabapentinoids on the acute inflammatory response of SDH primary cultures upon LPS stimulation. Such effects may contribute to the pain-relieving effects of gabapentinoids.
... Current evidence favors the existence of four isoforms of Cavα2δ subunit, only two of which (Cavα2δ1 and Cavα2δ2) bind gabapentin [2] in L-, N-and P/Q-type calcium channels [24,49]. This binding promotes inhibition of calcium inward currents [51] and, consequently, leads to a reduced release of glutamate [24,52,53] and other excitatory molecules such as substance P [24,54] and NMDA [55], with the expected attenuation of postsynaptic excitability [2,19,24,47,56,57]. In this study, we observed a similar inhibition of calcium influx in murine melanoma (non-excitable) cells treated with gabapentin. ...
Cancer pain may be the consequence of physical nerve compression by a growing tumor. We employed a murine model to study whether gabapentin was able to regulate tumor growth, in addition to controlling hyperalgesic symptoms. A fluorescent melanoma cell line (B16–BL6/Zs green) was inoculated into the proximity of the sciatic nerve in male C57BL/6 mice. The tumor gradually compressed the nerve, causing hypersensitivity. Tumor growth was characterized via in vivo imaging techniques. Every other day, gabapentin (100 mg/Kg) or saline was IP administered to each animal. In the therapeutic protocol, gabapentin was administered once the tumor had induced increased nociception. In the preventive protocol, gabapentin was administered before the appearance of the positive signs. Additionally, in vitro experiments were performed to determine gabapentin’s effects on cell-line proliferation, the secretion of the chemokine CCL2, and calcium influx. In the therapeutically treated animals, baseline responses to noxious stimuli were recovered, and tumors were significantly reduced. Similarly, gabapentin reduced tumor growth during the preventive treatment, but a relapse was noticed when the administration stopped. Gabapentin also inhibited cell proliferation, the secretion of CCL2, and calcium influx. These results suggest that gabapentin might represent a multivalent strategy to control cancer-associated events in painful tumors.
... The results highlight some findings that indicate that gabapentin is more effective in people with a history of alcohol withdrawal (9). Gabapentin is an aminoacid designed as a structural analogue of GABA (10) interacting with type 1 alpha-2-delta subunit of closed voltage calcium channels (11,12) and selectively inhibits the influx of calcium (13) which results in decreased ability to reduce postsynaptic excitability (14). By blocking excitatory neurotransmission, gabapentin increases the concentration of GABA in the brain (15,16). ...
... Gabapentin displays its anticonvulsant properties by hindering the functioning of presynaptic voltage-gated sodium and calcium channels and, in turn, reducing exocytosis and neurotransmitter release in order to reduce neural transmission. [6][7][8][9][10] Gabapentin also hinders the formation of new synapses by attaching to the α2δ1 subunit of calcium channels, and therefore blocks the interaction between thrombospondins (released by glia cells) and the α2δ1 subunit, which consequently inhibits the promotion of excitatory synapses. 11,12 Gabapentin has been marketed as a medication with a low side effect and toxicity profile. ...
Background: Alcohol and tobacco use disorders are pervasive health problems without adequate treatment. Gabapentin has been used for different psychiatric disorders, including addiction. Methods: In this article, the use of gabapentin for the treatment of alcohol and tobacco use disorders is reviewed. Accordingly, a database search of PubMed was performed (January 1, 1983-August 31, 2017), using the search terms "gabapentin" AND "alcohol" OR "tobacco". Animal and human studies written in English were included. A total of 426 records were identified, and 40 articles met eligibility criteria and were included in this review. The main reasons for exclusion were gabapentin was not the intervention of interest or the study population did not have alcohol/tobacco abuse issues. Additionally, 28 references were included in the Introduction, for a total of 68 references. The success of gabapentin for treating alcohol/tobacco use problems was determined by calculating the success rate across studies: the total number of investigations with favorable results was divided by the total numbers of investigations for each specific disorder (eg, alcohol or tobacco dependence, or other). Results and Discussion: The available evidence on gabapentin for alcohol use disorder suggests that this treatment successfully alleviates problems related to alcohol abuse, including withdrawal symptoms, dependence, and cravings. However, more research is needed to determine the effectiveness of gabapentin for preventing relapse. Further, more data are required before a conclusion regarding gabapentin's effectiveness for treating tobacco dependence.
... Gabapentin is an anticonvulsant drug that decreases neuronal transmission by inhibiting presynaptic voltage-gated calcium and sodium channels (Dickenson & Ghandehari, 2007;Landmark, 2007;Rogawski & Loscher, 2004), thus inhibiting exocytosis and the release of neurotransmitters from presynapses (Coderre, Kumar, Lefebvre, & Yu, 2007;Cunningham, Woodhall, Thompson, Dooley, & Jones, 2004). Moreover, Gabapentin inhibits synaptogenesis by binding to α2δ1 subunit of calcium channels (Bauer, Tran-Van-Minh, Kadurin, & Dolphin, 2010;Eroglu et al., 2009); specifically, Gabapentin antagonizes the interaction between α2δ1 subunit and glial released thrombospondins, hence inhibiting the promotion of excitatory synapses. ...
The study reviews the suitability of using Gabapentin for treating opioid, cannabis and methamphetamine use disorders. This revision consists of 61 biographical references based on a PubMed database search (January of 1983-May of 2018). Gabapentin displayed respectively 50% and 66.7% of success for treating methamphetamine dependence and opioid withdrawal symptoms. Furthermore, a few research studies have reported Gabapentin's efficacy for alleviating cannabis dependence (two studies), and cannabis withdrawal symptoms (one study). Similarly, a single study reported Gabapentin reduction of opioid consumption during the detoxification process. Based on the revision, we can conclude that: (a) Gabapentin is useful for treating opioid withdrawal symptoms, (b) additional studies are necessary for elucidating the effectiveness of Gabapentin for treating methamphetamine dependence, cannabis dependence and its withdrawal symptoms, and (c) more studies are necessary to confirm the efficacy of Gabapentin in reducing opioid consumption during detoxification.
... Gabapentin is an anticonvulsant drug that decreases neuronal transmission by inhibiting presynaptic voltage-gated calcium and sodium channels (Dickenson & Ghandehari, 2007;Landmark, 2007;Rogawski & Loscher, 2004), thus inhibiting exocytosis and the release of neurotransmitters from presynapses (Coderre, Kumar, Lefebvre, & Yu, 2007;Cunningham, Woodhall, Thompson, Dooley, & Jones, 2004). Moreover, Gabapentin inhibits synaptogenesis by binding to α2δ1 subunit of calcium channels (Bauer, Tran-Van-Minh, Kadurin, & Dolphin, 2010;Eroglu et al., 2009); specifically, Gabapentin antagonizes the interaction between α2δ1 subunit and glial released thrombospondins, hence inhibiting the promotion of excitatory synapses. ...
The study reviews the suitability of using Gabapentin for treating opioid, cannabis and methamphetamine use disorders. This revision consists of 61 biographical references based on a PubMed database search (January of 1983-May of 2018). Gabapentin displayed respectively 50% and 66.7% of success for treating methamphetamine dependence and opioid withdrawal symptoms. Furthermore, a few research studies have reported Gabapentin´s efficacy for alleviating cannabis dependence (two studies), and cannabis withdrawal symptoms (one study). Similarly, a single study reported Gabapentin reduction of opioid consumption during the detoxification process. Based on the revision, we can conclude that: (a) Gabapentin is useful for treating opioid withdrawal symptoms, (b) additional studies are necessary for elucidating the effectiveness of Gabapentin for treating methamphetamine dependence, cannabis dependence and its withdrawal symptoms, and (c) more studies are necessary to confirm the efficacy of Gabapentin in reducing opioid consumption during detoxification.
... Although inhibition of presynaptic calcium channels with a consequent reduction in release of excitatory neurotransmitter is an appealing mechanism to explain the antiseizure activity of gabapentinoids, the experimental evidence is not supportive. Nevertheless, there are studies that demonstrate an inhibition of excitatory synaptic potentials at brain synapses, but the mechanism is obscure (Cunningham et al., 2004;Dooley et al., 2007). Recent studies indicate that α2δ-1 associates with other proteins, including NMDA receptors (Chen et al., 2018b). ...
Antiseizure drugs (ASDs) prevent the occurrence of seizures; there is no evidence that they have disease-modifying properties. In the more than 160 years that orally administered ASDs have been available for epilepsy therapy, most agents entering clinical practice were either discovered serendipitously or with the use of animal seizure models. The ASDs originating from these approaches act on brain excitability mechanisms to interfere with the generation and spread of epileptic hyperexcitability, but they do not address the specific defects that are pathogenic in the epilepsies for which they are prescribed, which in most cases are not well understood. There are four broad classes of such ASD mechanisms: (1) modulation of voltage-gated sodium channels (e.g. phenytoin, carbamazepine, lamotrigine), voltage-gated calcium channels (e.g. ethosuximide), and voltage-gated potassium channels [e.g. retigabine (ezogabine)]; (2) enhancement of GABA-mediated inhibitory neurotransmission (e.g. benzodiazepines, tiagabine, vigabatrin); (3) attenuation of glutamate-mediated excitatory neurotransmission (e.g. perampanel); and (4) modulation of neurotransmitter release via a presynaptic action (e.g. levetiracetam, brivaracetam, gabapentin, pregabalin). In the past two decades there has been great progress in identifying the pathophysiological mechanisms of many genetic epilepsies. Given this new understanding, attempts are being made to engineer specific small molecule, antisense and gene therapies that functionally reverse or structurally correct pathogenic defects in epilepsy syndromes. In the near future, these new therapies will begin a paradigm shift in the treatment of some rare genetic epilepsy syndromes, but targeted therapies will remain elusive for the vast majority of epilepsies until their causes are identified.
... Importantly, it might be a factor that can be therapeutically targeted. For example, pregabalin, which blocks the voltage-dependent calcium channel and involved in glutamate release through an increase in Ca 21 influx, 8,12 has been shown to reduce glutamate levels in the posterior insula of patients with FM, 19 and memantine, an NMDA receptor antagonist, improved symptoms in FM compared with placebo. 34 ...
An imbalance between excitatory and inhibitory neurotransmission has been linked to Fibromyalgia (FM). Magnetic resonance spectroscopy (MRS) has shown increased levels of glutamate in the insula and posterior cingulate cortex in FM as well as reduced insular levels of GABA. Both of these changes have been associated with increased pain sensitivity. However, it is not clear whether excitatory and/or inhibitory neurotransmission is altered across the brain. Therefore, the aim of this study was to quantify GABAA receptor concentration on the whole brain level in FM to investigate a potential dysregulation of the GABAergic system.51 post-menopausal women (26 FM, 25 matched controls) underwent assessments of pain sensitivity, attention and memory, psychological status and function as well as positron emission tomography imaging using a tracer for GABAA receptors, [F]flumazenil. Patients showed increased pain sensitivity, impaired immediate memory and increased cortical GABAA receptor concentration in the attention and default-mode networks. No decrease of GABAA receptor concentration was observed. Across the two groups, GABAA receptor concentration correlated positively with functional scores and current pain in areas overlapping with regions of increased GABAA receptor concentration.This study shows increased GABAA receptor concentration in FM, associated with pain symptoms and impaired function. The changes were widespread and not restricted to pain-processing regions. These findings suggest that the GABAergic system is altered, possibly indicating an imbalance between excitatory and inhibitory neurotransmission. Future studies should try to understand the nature of the dysregulation of the GABAergic system in FM as and in other pain syndromes.
... However, we can speculate that gabapentinoids primarily acting on a 2 d 1 -subunit of the voltage-gated calcium (Ca 2+ ), reduce neuronal calcium influx at the pre-synaptic nerve (Fink et al., 2002;Bian et al., 2006). This reduction in calcium influx results in an inhibition of the release of neurotransmitters, including norepinephrine (Dooley et al., 2000;Dooley et al., 2002); substance P ; and glutamate Cunningham et al., 2004) and thereby attenuates neuronal excitability associated with sensory transmission. Through its active compounds Noxiall ® , instead, engages several biological systems as described above exerting anti-inflammatory, immune suppressant and anti-oxidant effects which work to attenuate the chronic stage of NP (Dolara et al., 1996;Esposito et al., 2012;Hesselink and Hekker, 2012;Passavanti et al., 2017;Segat et al., 2017). ...
Neuropathic pain (NP) is a common public health problem that poses a major challenge to basic scientists and health-care providers. NP is a complex problem with an unclear etiology and an often-inadequate response to current medications. Despite the high number of drugs available, their limited pharmacological efficacy and side effects hamper their chronic use. Thus, the search for novel treatments is a priority. In addition to pharmaceuticals, natural extracts and food supplements are often used to help to treat patients with NP. One such supplement is Noxiall®, a commercially available combination of N-Palmitoylethanolamide (PEA), beta-caryophyllene; carnosic acid and myrrh. Here, we compare the efficacy of Noxiall® to that of the medications gabapentin and pregabalin in the NP model of chronic constriction injury (CCI) using sciatic nerve ligation in mouse. Following CCI, mice developed a significant increase in mechanical allodynia and thermal hyperalgesia. Results showed that administration of either Noxiall®, pregabalin, or gabapentin significantly attenuated mechanical allodynia. The magnitude of the Noxiall® effect was comparable to that of gabapentin or pregabalin. In addition, co-administration of non-effective doses of pregabalin and Noxiall® resulted in a significant decrease in NP, suggesting an additive efficacy. Noxiall® was efficacious also in reducing CCI-induced thermal hyperalgesia. These findings support the rationale of using natural remedies in conjunction with classical pharmacological agents to treat chronic NP.
... An effective add-on therapy combined with methadone or buprenorphine is pregabalin and gabapentin, which are approved for treatment of epilepsy, neuropathic pain, or fibromyalgia [124]. These medications do not act directly on GABA receptors or transporters [125] but modulate the α2-delta subunit of calcium channels, preventing the release of neurotransmitters like glutamate [126]. Both medications prevent opioid tolerance and dependence and reduce withdrawal symptoms in humans and preclinical models [127][128][129]. ...
... Gabapentin was developed to create an analogue to GABA (Maneuf et al., 2006), but it does not act on GABA receptors or transporters (Taylor et al., 1998;Lanneau et al., 2001;Cheng et al., 2004). In fact, gabapentin inhibits calcium and sodium channels and prevents the release of neurotransmitters like glutamate (Cunningham et al., 2004). Studies by Anton et al. (2009Anton et al. ( , 2011 have suggested the efficacy of gabapentin in alcohol dependence, abstinence and acute alcohol withdrawal. ...
Addiction pharmacotherapy aims to prevent drug abstinence symptoms, reduce drug craving and relapse, and normalize physiologic functions disrupted by chronic use of the drug. During the last 50 years, there has been an enormous revolution in pharmacotherapy for drug addiction. From abstinence as practically the only treatment option available, there are now multiple drugs on the market that have proved their efficacy in treating opiate and alcohol disorders. The present review will focus on the pharmacological treatments of the drugs whose consumption most affects individuals and society: alcohol and opiates. We will review the drugs most widely prescribed to prevent relapse and maintain abstinence, as well as those designed to reduce the consumption of short-acting drugs (e.g. maintenance therapies) since the 1960s. Methadone and buprenorphine are the most widely used maintenance therapies for opiate addicts, although new pharmacological depot systems of naltrexone are showing promising results. For alcohol use disorders, acamprosate, nalmelfene and naltrexone are replacing disulfiram prescriptions, and a wide variety of new products are currently under study. The number of new pharmacological targets already on clinical trials and the advanced new ways to administer classic therapies can improve the success rate of the pharmacotherapy for opioid and alcohol addiction.
... Men de hadde antiepileptiske egenskaper, trolig ved en binding til en subenhet (α2δ) i spenningsstyrte kalsiumkanaler. Bindingen påvirker den presynaptiske frigjøringen av transmittere, blant annet glutamat (16). ...
... Gabapentinoids (GBP and pregabalin) may decrease functional excitatory synaptic connectivity and epileptiform activity in the UC model through several mechanisms. GBP binds with high affinity to α2δ-1 auxiliary subunits of L-type VGCC (Gee et al. 1996;Dooley et al. 2007;Li et al. 2011; and is primarily expressed in presynaptic terminals of excitatory cells (Cole et al. 2005), where it may have acute effects on transmitter release (van Hooft et al. 2002;Cunningham et al. 2004;Brown and Randall 2005;Dooley et al. 2007;Micheva and Smith 2007;Taylor et al. 2007). The α2δ proteins are thought to be involved in calcium channel trafficking, and chronic GBP administration in cultures interferes with α2δ and reduces the surface expression and current density of calcium channels, associated with a reduction in synaptic activity (Hendrich et al. 2008;Tran-Van-Minh and Dolphin 2010;Hoppa et al. 2012). ...
Neocortical injury initiates a cascade of events, some of which result in maladaptive epileptogenic reorganization of surviving neural circuits. Research focused on molecular and organizational changes that occur following trauma may reveal processes that underlie human post-traumatic epilepsy (PTE), a common and unfortunate consequence of traumatic brain injury. The latency between injury and development of PTE provides an opportunity for prophylactic intervention, once the key underlying mechanisms are understood. In rodent neocortex, injury to pyramidal neurons promotes axonal sprouting, resulting in increased excitatory circuitry that is one important factor promoting epileptogenesis. We used laser-scanning photostimulation of caged glutamate and whole-cell recordings in in vitro slices from injured neocortex to assess formation of new excitatory synapses, a process known to rely on astrocyte-secreted thrombospondins (TSPs), and to map the distribution of maladaptive circuit reorganization. We show that this reorganization is centered principally in layer V and associated with development of epileptiform activity. Short-term blockade of the synaptogenic effects of astrocyte-secreted TSPs with gabapentin (GBP) after injury suppresses the new excitatory connectivity and epileptogenesis for at least 2 weeks. Results reveal that aberrant circuit rewiring is progressive in vivo and provide further rationale for prophylactic anti-epileptogenic use of gabapentinoids following cortical trauma.
... It is believed that blockade of VGCC containing the α2δ-1 subunit is the predominant pharmacological mechanism of both GBP and PGB (16). PGB binds potently to the α2δ-1 subunit and modulates calcium influx at nerve terminals, thereby, reducing the release of several neurotransmitters, including glutamate, noradrenaline, serotonin and SP (17)(18)(19). Interestingly, GBP could be a therapeutic agent, when given systemically, for treatment of neuropathic or postsurgical pain (20)(21)(22)(23)(24), and also reduces the experimental pain in humans after sensitization of the skin with capsaicin and heat (25). Furthermore, GBP and its derivative PGB reduce nociceptive behaviors of animal models with neuropathic pain or inflammation such as nerve ligation, injection of immune antigens, herpes infection, arthritis, diabetes, postoperative pain and thermal injury (26)(27)(28)(29)(30). ...
Gabapentin (GBP) and pregabalin (PGB) exert antinociceptive effects on chronic nociceptive responses with neuropathic or inflammatory conditions. Furthermore, it is considered that GBP and PGB exhibit anti‑inflammatory effects by modulating the substance P (SP)‑mediated neurokinin‑1 receptor (NK1R; a SP receptor) response. Thus, in the present study, the effects of GBP and PGB on SP‑induced activation were investigated in the human glioblastoma astrocytoma U373 MG cell line, which expresses high levels of functional high‑affinity NK1R, and produces interleukin (IL)‑6 and IL‑8 in response to SP. The results indicated that GBP and PGB suppressed the SP‑induced production of IL‑6, and IL‑8 in U373 MG cells. Furthermore, GBP and PGB inhibited the SP‑induced phosphorylation of p38 mitogen‑activated protein kinase (MAPK) and nuclear factor (NF)‑κB, and the nuclear translocation of NF‑κB in U373 MG cells. Together, these observations suggest that GBP and PGB likely prevent SP‑induced IL‑6 and IL‑8 production in U373 MG cells via the inhibition of signaling molecules, including p38 MAPK and NF‑κB, thereby exhibiting antineuroinflammatory effects.
... Together these characteristics would permit subthreshold modulation of excitability by Ca V 2.1 in S218L mice, providing a potential mechanism underlying the more severe phenotype in this strain. Pregabalin has a direct inhibitory effect on calcium-mediated glutamate release in brain slices from neocortex (41) and entorhinal cortex (42). In addition, pregabalin displays two-to threefold enhanced efficacy in the depression of noradrenaline release upon sustained depolarization as compared with brief stimulation (26,43). ...
Significance
Spreading depression is proposed to underlie migraine with aura, a type of debilitating headache for which few pharmacological treatments are available. The pain drug pregabalin has demonstrated initial promising results for the treatment of migraine in the clinic. Utilizing animal models of congenital migraine and live brain imaging, we describe the cortical and subcortical migration of the spreading depression wave. Further, pregabalin is shown to be effective at suppressing spreading depression initiation, wave speed, and subcortical propagation, and also to affect nerve cell signalling directly. Overall, the study supports the therapeutic potential of pregabalin in both noncongenital migraineurs and patients with mild congenital migraine.
... [2][3][4] Besides, gabapentin reduces exocytosis and the discharge of neurotransmitter from presynaptic terminals. 5,6 On the other hand, another line of research reported that gabapentin decreases the formation of excitatory synapses by acting on α2-δ1 subunit of calcium channels. 7,8 Besides, complementary research pointed out that gabapentin has specific affinity for α2-δ1 subunit, lower affinity for α2-δ2 subunit and non-affinity for α2-δ3 subunits. ...
The current work is targeted to review the risks of gabapentin misuse, its potential interactions with other drugs, side effects and use contraindications. This review consists of a total of 99 biographical references (from the year 1983 to 2016). A publication search of PubMed was performed from January 1983 to December 2016. It included animal studies, clinical studies, case studies and reviews related to gabapentin misuse, potential interactions, side effects and use contraindications. The search terms were gabapentin, anticonvulsant and antiepileptic. In general, it seems that gabapentin has risks of being misused based on the increased level of prescriptions, related fatalities, recreational misuse and higher doses of self-administration. The main reasons for gabapentin misuse are as follows: getting high, alleviating opioid withdrawal symptoms and potentiating methadone effects. Some of the main substances that interact with gabapentin are morphine, caffeine, losartan, ethacrynic acid, phenytoin, mefloquine and magnesium oxide. Some of the side effects caused by gabapentin are teratogenicity, hypoventilation, respiratory failure and myopathy. Finally, reports in general contraindicate the use of gabapentin in conditions such as myasthenia gravis and myoclonus.
... Studies have shown inhibitory effects on voltage-gated Ca 2+ currents that can selectively block either P/Q-or N-type Ca 2+ channels [35]. Other studies have shown inhibition of the release of neurotransmitters [36]. Gabapentin and pregabalin inhibit neurotransmitter release in many systems mainly by interaction of α2-δ with synaptic proteins that are involved in the release or trafficking of synaptic vesicles rather than inhibition of calcium influx [4]. ...
Different mechanisms of action have been proposed to explain the effects of antiepileptic drugs (AEDs) including modulation of voltage‐dependent sodium calcium and potassium channels, enhancement of γ‐aminobutyric acid (GABA)‐mediated neuronal inhibition, and reduction in glutamate‐mediated excitatory transmission. Recent advances in understanding the physiology of ion channels and genetics basis of epilepsies have given insight into various molecular targets for AEDs. Conventional AEDs predominantly target voltage‐ and ligand‐gated ion channels including the α subunits of voltage‐gated Na⁺ channels, T‐type, and α2‐δ subunits of the voltage‐gated Ca²⁺ channels, A‐ or M‐type voltage‐gated K⁺ channels, the γ‐aminobutyric acid (GABA) receptor channel complex, and ionotropic glutamatergic receptors. Molecular cloning of ion channel subunit proteins and studies in epilepsy models suggest additional targets including hyperpolarization‐activated cyclic nucleotide‐gated cation (HCN) channel subunits, responsible for hyperpolarization‐activated current (Ih), voltage‐gated chloride channels, and acid‐sensing ion channels. This chapter gives an update on voltage‐ and ligand‐gated ion channels, discussing their structures, functions, and relevance as potential targets for AEDs.
... Gabapentin is an anticonvulsant medication that disrupts neuronal transmission by inhibition of presynaptic voltage-gated Na+ and Ca2+ channels [90][91][92]. Consequently, gabapentin acts to inhibit the release of various neurotransmitters, including glutamate [93][94][95][96][97][98][99]. While studies have found that gabapentin is effective in mitigating the symptoms of alcohol withdrawal due to moderate to severe CNS hyperexcitability and convulsions [100][101][102][103][104][105][106][107], its role as antidrug abuse agent remains questionable. ...
Willuhn et al. observed that habitual cocaine use was correlated with reductions in D2/D3 receptors linked to decreased cue activation in occipital cortex and cerebellum. Dopamine agonist therapy maintains dopamine function and is relapse prevention tactic focused on psychoactive drug and behavioral addictions. Medication Assisted Treatment (MAT) with emphasis on glutaminergic medications fails in the long-term treatment of Reward Deficiency Syndrome Behaviors (RDS). While the careful use of "dopamine antagonist-therapy" short-term is supported, the research-based concept of "dopamine agonist therapy" in long-term is proposed. Neurogenetics and epigenetics are important in understanding treatment response and clinical outcomes. The neuro-mechanisms involving "dopamine homeostasis" are key to understanding recovery from drug and non-drug addictive behaviors. For example, patients who carry the DRD2 A1 allele (30-40 less D2 receptors) should consider Neuronutriant-Amino-Acid therapy (KB220 variants) a prevention modality. DRD2 A1 allele carriers show amplified striatal function of L-amino acid decarboxylase, prior to dopamine biosynthesis. Another example is the effect of Acute Tyrosine Phenylalanine Depletion (ATPD) on decision-making and reward found carriers with amino-acid deficiency (ATPD). They experienced attenuated reward and reduced decision-making ability as quantified by Iowa Gambling Task (IGT). Future research should be directed at asking the question; Would "dopamine agonist therapy" using KB220 variants reduce methylation and increase acetyl groups to enhance DRD2 expression especially in DRD2 A1 allele carriers and lead to increased dopamine function and a reduction of drug and non-drug seeking behaviors.
... 30 The final effect is a reduction of tonic release of several neurotransmitters, both excitatory and inhibitory, including GABA, which alters neuronal responsiveness leading to reduction of hyperexcitability in pain processing pathway. 31 Pregabalin is rapidly absorbed after oral administration with a mean oral bioavailability of 90%. 32 Time to reach maximum plasma concentration is 0.7-1.3 ...
Fibromyalgia is a chronic debilitating medical syndrome with limited therapeutic options. Pregabalin, an anticonvulsant and α-2-Δ subunit receptor ligand, is one of the anchor drugs approved by the US Food and Drug Administration for the treatment of fibromyalgia. The drug has shown clinically meaningful benefits across multiple symptom domains of fibromyalgia. Efficacy of pregabalin in fibromyalgia pain has been evaluated in at least five high-quality randomized trials, two long-term extension studies, a meta-analysis, a Cochrane database systematic review, and several post hoc analyses. These studies also hint towards a meaningful benefit on sleep, functioning, quality of life, and work productivity. Side effects of pregabalin, although common, are mild to moderate in intensity. They are noted early during therapy, improve or disappear with dose reduction, and are not usually life- or organ threatening. In most patients, tolerance develops to the most common side effects, dizziness, and somnolence, with time. With close clinical monitoring at initiation or dose titration, pregabalin can be effectively used in primary care setting. Pregabalin is cost saving with long-term use and its cost-effectiveness profile is comparable, if not better, to that of other drugs used in fibromyalgia. In the present era of limited therapeutic options, pregabalin undoubtedly retains its role as one of cardinal drugs used in the treatment of fibromyalgia. This review intends to discuss the clinical utility of pregabalin in the management of fibromyalgia with a focus on efficacy, safety, and cost-effectiveness.
Substance abuse is a worldwide problem with serious repercussions for patients and the communities where they live. Pregabalin (Lyrica), is a medication commonly used to treat neuropathic pain. Like other analgesic medications there has been concern about pregabalin abuse and misuse. Although it was initially suggested that pregabalin, like other gabapentinoids, has limited abuse liability, questions still remain concerning this inquiry. Changes in glutamate system homeostasis are a hallmark of adaptations underlying drug dependence, including down-regulation of the glutamate transporter 1 (GLT-1; SLC1A2) and the cystine/glutamate antiporter (xCT; SLC7A11). In this study, it was found that pregabalin (90 mg/kg) produces a conditioned place preference (CPP), indicative of reinforcing effects that suggest a potential for abuse liability. Moreover, like other drugs of abuse, pregabalin also produced alterations in glutamate homeostasis, reducing the mRNA expression of Slc1a2 and Slc7a11 in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). Amoxicillin clavulanic acid, a β-lactam antibiotic, blocked the reinforcing effects of pregabalin and normalized glutamate homeostasis. These results suggest that pregabalin has abuse potential that should be examined more critically, and that, moreover, the mechanisms underlying these effects are similar to those of other drugs of abuse, such as heroin and cocaine. Additionally, these results support previous findings showing normalization of glutamate homeostasis by β-lactam drugs that provides a novel potential therapeutic approach for the treatment of drug abuse and dependence.
Duchenne muscular dystrophy (DMD) is an X‐linked genetic disorder induced by mutations in the dystrophin gene, leading to a degeneration of muscle fibers, triggering retrograde immunomodulatory, and degenerative events in the central nervous system. Thus, neuroprotective drugs such as pregabalin (PGB) can improve motor function by modulating plasticity, together with anti‐inflammatory effects. The present work aimed to study the effects of PGB on axonal regeneration after axotomy in dystrophic and non‐dystrophic mice. For that, MDX and C57BL/10 mouse strains were subjected to peripheral nerve damage and were treated with PGB (30 mg/kg/day, i.p.) for 28 consecutive days. The treatment was carried out in mice as soon as they completed 5 weeks of life, 1 week before the lesion, corresponding to the peak period of muscle degeneration in the MDX strain. Six‐week‐old mice were submitted to unilateral sciatic nerve crush and were sacrificed in the 9th week of age. The ipsi and contralateral sciatic nerves were processed for immunohistochemistry and qRT–PCR, evaluating the expression of proteins and gene transcripts related to neuronal and Schwann cell activity. Cranial tibial muscles were dissected for evaluation of neuromuscular junctions using α‐bungarotoxin, and the myelinated axons of the sciatic nerve were analyzed by morphometry. The recovery of motor function was monitored throughout the treatment through tests of forced locomotion (rotarod) and spontaneous walking track test (Catwalk system). The results show that treatment with PGB reduced the retrograde cyclic effects of muscle degeneration/regeneration on the nervous system. This fact was confirmed after peripheral nerve injury, showing better adaptation and response of neurons and glia for rapid axonal regeneration, with efficient muscle targeting and regain of function. No side effects of PGB treatment were observed, and the expression of pro‐regenerative proteins in neurons and Schwann cells was upregulated. Morphometry of the axons was in line with the preservation of motor endplates, resulting in enhanced performance of dystrophic animals. Overall, the present data indicate that pregabalin is protective and enhances regeneration of the SNP during the development of DMD, improving motor function, which can, in turn, be translated to the clinic.
Glutamate appears to be a critical neurotransmitter in the neurocircuitry and neurophysiology of aggressive behaviors in mammals including humans. Animal models help to clarify the neurocircuitry of both defensive and predatory aggression. Together with other neurotransmitters, glutamate is involved in the medial amygdala–mediobasal hypothalamus–dorsal periaqueductal gray pathway which triggers defensive aggression in animal models and impulsive aggression in humans. CSF glutamate levels are shown to be elevated in humans with impulsive aggression. The growing knowledge about glutamate’s potential role in abnormal impulsive aggression may help to explain antiaggressive mechanisms of action of anti-impulsive aggression and antipsychotic agents as well as memantine, an N-methyl-D- aspartate antagonist, through restoration of a glutamate/GABA imbalance.
Seizures are sudden events of hyper-active and/or hyper-synchronous brain activity that result in a variety of experiences and behavioral manifestations that may include motor convulsions. Epilepsy is a chronic state of recurring multiple spontaneous seizures and is one of the most common neurological health problems world-wide. It is estimated that half of all Epilepsy cases are due to a combination of genetic and environmental factors whereas the remaining 50% of cases are of unknown (or unverified) origin. It is further estimated that almost ~ 3/4 of individuals living with Epilepsy could experience effective seizure management if given access to appropriate clinical diagnostics and treatment. Further research efforts for Epilepsy are needed including to provide effective treatments for remaining ~ 1/4 of individuals living with Epilepsy who experience difficulties in seizure prevention and seizure control. Pharmacological therapies that reduce severity and frequency of seizures, often referred to as Anti-Seizure Medications (ASMs), are the predominant treatment approach to Epilepsy. This chapter will provide an overview of Epilepsy before describing key pharmacological properties of ASMs based (primarily by emphasizing pharmacokinetics and pharmacodynamics). This author acknowledges the amazing and essential efforts of the individuals affected by Epilepsy, their families, and the dedicated groups of clinical and preclinical professionals all working toward the safe elimination of Epilepsy and seizure syndromes world-wide.
Inhibiting glutamate release can reduce neuronal excitability and is recognized as a key mechanism of anti-epileptic drugs. In this study, by using isolated nerve terminal (synaptosome) and slice preparations, we investigated the effect of asiatic acid, a triterpene isolated from Centella asiatica with antiepileptic activity, on glutamate release in the hippocampus of rats. In hippocampal synaptosomes, application of asiatic acid resulted in a concentration-dependent inhibition of 4-aminopyridine-evoked glutamate release. This inhibitory action was dependent on extracellular calcium, blocked by inhibiting the vesicular transporter, but was unaffected by inhibiting the glutamate transporter. In addition, asiatic acid decreased the 4-aminopyridine-induced increase in the intraterminal calcium and failed to alter the synaptosomal potential. Furthermore, the asiatic acid-mediated release inhibition was significantly suppressed by the N- and P/Q-type calcium channel inhibitor ω-conotoxin MVIIC or protein kinase C inhibitor GF109203X. Western blotting data in synaptosomes also revealed that asiatic acid reduced 4-aminopyridine-induced phosphorylation of protein kinase C. In hippocampal slices, asiatic acid decreased the frequencies of spontaneous excitatory postsynaptic currents without changing their amplitudes and glutamate-activated currents in CA3 pyramidal neurons. We also observed that asiatic acid significantly suppressed 4-aminopyridine-induced burst firing. These data suggest that, in rat hippocampal nerve terminals, asiatic acid attenuates the calcium influx via N- and P/Q-type calcium channels, subsequently suppressing protein kinase C activity and decreasing glutamate release.
The monosodium iodoacetate (MIA)‐induced joint degeneration in rats is the most used animal model to screen analgesic drugs to alleviate osteoarthritis (OA) pain. This study aimed to evaluate the analgesic efficacy of pregabalin (PGB) in an MIA‐induced OA model in rodents by using functional and neuroproteomic pain assessment methods. Treatment group included PGB in curative intent over 9 days compared to gold standard therapy (positive controls) and placebo (negative control). Functional assessments of pain (quantitative sensory testing and operant test) were performed concomitantly with spinal neuropeptides quantification. At day 21 post‐OA induction, PGB in MIA rats reduced tactile allodynia (P = 0.028) and improved the place escape/avoidance behavior (P = 0.04) compared to values recorded at last time‐point before initiating analgesic therapy. All spinal neuropeptide concentrations, such as substance P, calcitonin gene‐related peptide, bradykinin and somatostatin, came back to normal (non affected) rat values, compared to their increase observed in MIA rats receiving the placebo (P < 0.0001). Initiated 13 days after chemical OA induction, repeated medication with PGB provided analgesia according to quantitative sensory testing, operant test and targeted neuropeptides pain assessment methods. This report highlights the interest of using reliable and sensitive methods like targeted neuropeptide quantification to detect the analgesic effects of a test article with concomitant functional assessments of pain when studying OA pain components.
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The last decade has seen a marked increase in the use of gabapentinoid drugs for pain management. This, in part, reflects the shift from some non-steroidal anti-inflammatory drugs (NSAIDs), as well as issues arising from the protracted use of opioids. More extensive use of gabapentin and pregabalin has seen the clinical role widen to incorporate a range of unlicensed pain scenarios, as well as increased medicines costs.
The evidence for efficacy in some pain conditions, namely post-herpetic neuralgia and diabetic neuropathic pain, is stronger than for non-neuropathic pain conditions, such as fibromyalgia. Anxiolytic properties, as well as widespread availability, have encouraged recreational misuse, which is associated with doses outside the therapeutic range.
Safe use for neuropathic pain (central and peripheral), complex pain, and migraine, and the evidence for some non-neuropathic pain conditions will be discussed, as well as the emerging abuse issues. Anti-convulsant interventions will not be covered in this article, nor will use in children.
Objectives: Pregabalin, an α2-δ agonist, is approved for the treatment of fibromyalgia (FM) in the United States, Japan, and 37 other countries. The purpose of this article was to provide an in-depth, evidence-based summary of pregabalin for FM as demonstrated in randomized, placebo-controlled clinical studies, including open-label extensions, meta-analyses, combination studies, and post-hoc analyses of clinical study data.
Methods: PubMed was searched using the term ‘pregabalin AND fibromyalgia’ and the Cochrane Library with the term ‘pregabalin’. Both searches were conducted on 2 March 2017 with no other date limits set.
Results: Eleven randomized, double-blind, placebo-controlled clinical studies were identified including parallel group, 2-way crossover, and randomized withdrawal designs. One was a neuroimaging study. Five open-label extensions were also identified. Evidence of efficacy was demonstrated across the studies identified with significant and clinically relevant improvements in pain, sleep quality, and patient status. The safety and tolerability profile of pregabalin is consistent across all the studies identified, including in adolescents, with dizziness and somnolence the most common adverse events reported. These efficacy and safety data are supported by meta-analyses (13 studies). Pregabalin in combination with other pharmacotherapies (7 studies) is also efficacious. Post-hoc analyses have demonstrated the onset of pregabalin efficacy as early as 1–2 days after starting treatment, examined the effect of pregabalin on other aspects of sleep beyond quality, and shown it is effective irrespective of the presence of a wide variety of patient demographic and clinical characteristics.
Conclusions: Pregabalin is a treatment option for FM; its clinical utility has been comprehensively demonstrated.
Introduction: Alcohol misuse is the fifth leading risk factor for premature death and disability worldwide. Fewer than 10% of afflicted Americans receive pharmacological treatment for alcohol use disorder. Gabapentin is a calcium channel GABAergic modulator that is widely used for pain. Studies showing reduced drinking and decreased craving and alcohol-related disturbances in sleep and affect in the months following alcohol cessation suggest therapeutic potential for alcohol use disorder.
Areas covered: Human laboratory and clinical studies assessing gabapentin for alcohol use disorder are reviewed. Data were obtained by searching for English peer-reviewed articles on PubMed, reference lists of identified articles, and trials registered on clinicaltrials.gov. Additionally, the mechanism of action of gabapentin specific to alcohol use disorder, and studies of gabapentin for alcohol withdrawal and non-alcohol substance use disorders are summarized.
Expert opinion: Alcohol use disorder represents a challenge and large, unmet medical need. Evidence from single-site studies lend support to the safety and efficacy of gabapentin as a novel treatment for alcohol use disorder, with unique benefits for alcohol-related insomnia and negative affect, relative to available treatments. Proprietary gabapentin delivery systems may open a path to pivotal trials and registration of gabapentin as a novel treatment for alcohol use disorder.
Introduction:
Only a few medications are available for the treatment of alcohol use disorders (AUDs).
Areas covered:
This paper discusses approved AUD medications, including the opioid antagonists; naltrexone and nalmefene (the latter is licensed for reduction of alcohol consumption only), the putative glutamate receptor antagonist acamprosate and the aldehyde dehydrogenase inhibitor disulfiram. It also covers off-label medications of interest, including topiramate, gabapentin, ondansetron, varenicline, baclofen, sodium oxybate and antidepressants. Clinical implications, benefits and risks of treatment are discussed.
Expert opinion:
Acamprosate, naltrexone, nalmefene and disulfiram are the only approved “alcohol-specific” drugs. Acamprosate and naltrexone have been evaluated in numerous clinical trials and represent evidence-based treatments in AUDs. Nalmefene use, however, is controversial. Supervised disulfiram is a second-line treatment approach. Compounds developed and licensed for different neuropsychiatric disorders are potential alternatives. Encouraging results have been reported for topiramate, gabapentin and also varenicline, which might be useful in patients with comorbid nicotine dependence. The GABA-B receptor agonist baclofen has been studied more intensively and shown mixed results; it is currently licensed for the treatment of AUDs in France only. Gabapentin may be close to approval in the USA. Further studies of these novel treatment approaches in AUDs are needed.
With increases in the prevalence of psychiatric and behavioral disorders and rapid advances in the development of new drug therapies, there is an increasing need to present the science behind these developments. Students and educators are often confronted with conflicting and exaggerated claims about the effectiveness of drugs. As recently as ten years ago, the mechanisms of action of many medications prescribed for common psychological disorders were not well understood, even by the scientists developing them. Now, drug treatment has advanced to a stage where drugs are designed for their effects on specific receptors, membrane proteins, or secondary messengers within particular cells in the brain. This text introduces a sufficient background in neuroanatomy and physiology so students can comprehend the necessary details of drug action. Psychopharmacology, Second Edition, presents its subject matter in the context of the behavioral disorders they are designed to treat, rather than by traditional drug classifications. Students are often familiar with the major diagnostic categories, so presenting psychopharmacology as it pertains to these familiar disorders strengthens their understanding of the physiology and neurochemistry underlying them as well as the approaches to their treatment. Each disorder is discussed from a historical context along with diagnostic criteria and descriptions of typical cases. In addition, what we presently know about the underlying pathology of each disorder is carefully described. A critical examination of drug claims is missing from most psychopharmacology texts, but is offered here. Students will read about the most current research available from a critical perspective. When alternatives to traditional drug therapies are supported by research, these studies are presented as well. Throughout, this text discusses how drug effectiveness is measured in both human and animal studies. Psychopharmacology has contributed significantly over the past 75 years to the treatment of severe psychological disorders as well as to our understanding of the brain and human behavior. This symbiotic relationship between psychopharmacology and the neural and behavioral sciences will continue long into the future. This fully updated second edition is ideal for undergraduate and pre-professional students, and includes a robust companion website.
Gabapentin (1-aminomethyl-cyclohexyl-acetic acid) is an amino acid derived by the addition of a cyclohexyl group to the backbone of γ-aminobutyric acid (GABA). Evidence on the use of gabapentin in non-epilepsy indications has been available from animal studies for over a decade. Gabapentin also has anxiolytic-like effects and can prevent the nociceptive responses from hyperalgesia. Gabapentin is absorbed from the small intestine through an active transport system, the L-amino acid transporter, which becomes saturated within the clinically used dose range. There are no interactions between gabapentin and hepatically cleared medications because gabapentin is not metabolized in the liver and does not induce or inhibit cytochrome P450 (CYP) drug-metabolizing enzyme systems or uridinediphosphoglucuronyl transferase (UGT) isoenzymes. Gabapentin has also been demonstrated to be effective in the treatment of alcohol dependence. Gabapentin is effective in focal epilepsies but may aggravate generalized epilepsies.
The gabapentinoins pregabalin and gabapentin are known as a2δ ligands due to their interaction with the Ca 2+ channel a2d subunit. They might act as inhibitory modulators of neuronal excitability that reduce ectopic neuronal activation of hyper-excited neurons while normal activation remains unchanged. Pregabalin has a wide range of indications but is also off-label prescribed for several disorders. Its prescribing grew rapidly reaching globally 5.1 billion dollars in 2013 but there is also an anecdotally growing black market through online pharmacies. Despite appropriate therapeutic indications, there are rising questions about pregabalin's, and to a lesser extent gabapentin's, abuse and dependence potential. Increasing evidence signaling pregabalin's abuse liability are published in controlled trials, queries, urine and serum screening studies and postmortem toxicological studies and the provenance of the majority of misuse appears to be from sources other than legitimately prescribed medication. However, a2δ ligand properties are not sufficient to account for the broad clinical spectrum of pregabalin effects including the abuse potential. The neural basis for its addictive nature remains poorly understood and its effect on the dopaminergic 'reward' should be clarified. The aim of this review is to present data signaling pregabalin's abuse liability reflecting on the pharmacological aspects that might enable this drug to trigger addictive behaviours .
Gabapentin is a federally non-scheduled anticonvulsant used in clinical practice for several neuropsychiatric conditions. Reports of abuse and descriptions of desirable effects experienced by users are frequent in the literature. The following case reports a patient with compulsive gabapentin abuse despite a lack of previously described desirable effects.
These practice guidelines for the biological treatment of alcohol use disorders are an update of the first edition, published in 2008, which was developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). For this 2016 revision, we performed a systematic review (MEDLINE/PUBMED database, Cochrane Library) of all available publications pertaining to the biological treatment of alcoholism and extracted data from national guidelines. The Task Force evaluated the identified literature with respect to the strength of evidence for the efficacy of each medication and subsequently categorised it into six levels of evidence (A-F) and five levels of recommendation (1-5). Thus, the current guidelines provide a clinically and scientifically relevant, evidence-based update of our earlier recommendations. These guidelines are intended for use by clinicians and practitioners who evaluate and treat people with alcohol use disorders and are primarily concerned with the biological treatment of adults with such disorders.
Cocaine potently increases monoaminergic neurotransmission by inhibitingpresynaptic dopamine, norepinephrine, and serotonin transporters. However, a wealth ofevidence now exists that implicates an important role of the excitatory amino acidneurotransmitter glutamate and its receptors in the rewarding and reinforcing effects ofcocaine. Glutamatergic neurotransmission also appears to be involved in the extinction ofand relapse to cocaine-seeking.This chapter will review the clinical efficacy of medications with glutamatergicmechanisms of action for the treatment of cocaine addiction. Evidence from preclinicalanimal studies demonstrating potential efficacy of novel glutamatergic compounds for thetreatment of cocaine addiction will also be reviewed.
Aim
Neuropathic pain is the most prominent complication of diabetes mellitus. In diabetic
neuropathy (DN), pain often remains unresponsive to available drugs. In diabetic neuropathy
increase in Na+ channel accumulation and ROS have been reported which causes nerve damage
and responsible for hyperalgesia, allodynia and increased oxidative stress. Hence the present
study was designed to investigate the effect of carbamazepine (Na channel blocker) and
melatonin (an antioxidant) alone and in combination on streptozotocin (STZ) induced diabetic
peripheral neuropathy (DPN) in Wistar rats.
Materials and Methods
Wistar rats (n = 6) of either sex weighing 150-200g were employed in the present study. Blood
glucose level (BGL), and all other parameters were measured before and after 4 weeks of
injecting streptozotocin (50mg/kg i.p, once). Rats with BGL above 200mg/dl were considered as
diabetic and included for further study. Parameter employed are GOD-POD method, thermal and
mechanical hyperalgesia, cold allodynia and TBARS, nitrite and GSH level.
Result
The low dose combination of carbamazepine (15 mgkg-1) and melatonin (100 μgkg-1)
significantly decreased pain and oxidative stress than carbamazepine (15, 30 mgkg-1) and
melatonin (100, 200 μgkg-1) alone.
Conclusion
Thus low dose combinations exert synergistic effect in inhibiting STZ- induced DN pain.
Não há conflitos de interesse. Todos os direitos editoriais adquiridos. Artigo recebido em: 02 de Agosto de 2014. Artigo aceito em: 12 de Outubro de 2014. RESUMO INTRODUÇÃO: A esclerose múltipla é u m a d o e n ç a a u t o i m u n e d e c a r á t e r progressivo no SNC (Sistema Nervoso C e n t r a l). O m o d e l o d e E A E (Encefalomielite Autoimune Experimental) é capaz de reproduzir a patogenicidade da esclerose múltipla associada à resposta i m u n i t á r i a. O s l i n f ó c i t o s T encefalitogênicos têm papel importante na esclerose múltipla e tem-se tentado modular essas células através de estratégias terapêuticas. A pregabalina é um fármaco análogo ao ácido gama-aminobutírico (GABA) que atua como anticonvulsivante, o qual reduz a liberação de noradrenalina e glutamato, bem como tem a capacidade de modular a transmissão sináptica excitatória e promover efeitos antiapoptóticos e anti-inflamatórios. OBJETIVOS: Analisar morfologicamente, in vitro, a neuroproteção promovida pela pregabalina em culturas de células neuronais com meio condicionado contendo linfócitos T encefalitogênicos. MÉTODOS: Camundongos C57BL/6 fêmeas de seis semanas de idade foram induzidos para EAE. Decorridos dez dias da Pregabalina protege neurônios da ação pró-inflamatória de linfócitos T encefalitogênicos. Pregabalin protects neurons of pro-inflammatory action of the T lymphocytes encephalitogenic. Palavras-chave: Encefalomielite Autoimune Experimental; Sistema Nervoso Central; Técnicas de Cultura de Células; Pregabalina.
Andrew J Thorpe, PhD, is a Director in the Department of CNS and Inflammation Chemistry, Pfizer Global Research and Development, Ann Arbor, MI, USA. He obtained his BSc in Medicinal Chemistry from University College London in 1990 and a PhD in organic synthesis from the University of Exeter in 1993, working under the guidance of Prof Stanley M Roberts, where his focus was on the synthesis of novel nucleoside analogs. From Exeter he moved to a Postdoctoral Research Associate position with Prof Tomas Hudlicky at Virginia Polytechnic Institute and State University and later at the University of Florida, where he studied the chemistry of cyclohexadiene-cis-diols. After his research in the Hudlicky group, he moved to Eli Lilly and Company where he served as a Postdoctoral Research Fellow under the mentorship of Tony Shuker in Endocrine Research. He then joined Parke-Davis Research (now Pfizer Global Research and Development) in Ann Arbor, Michigan in the CNS department where he studied the chemistry and pharmacology of α2–δ ligands. His research experience is extended beyond CNS and incorporates that of inflammatory diseases.
The relationship between epileptiform events in the medial entorhinal cortex (MEC) and the dentate gyrus was investigated using a slice preparation from rat brain. Simultaneous intracellular recordings were made from neurones in layer II of the MEC and neurones in the granule cell layer of the dentate gyrus (DGC). Epileptiform activity was induced by perfusion with Mg+(+)-free medium or GABAA-receptor blockers. Epileptiform discharges in MEC cells were reflected on a one-to-one basis and at a latency of 1-3 ms by depolarizing events in DGC. The latter rarely gave rise to action potentials. Bath perfusion of the N-methyl-D-aspartate (NMDA) receptor blocker, 2-aminophosphonovalerate (2-AP5) abolished the Mg+(+)-free induced events in MEC cells and the corresponding depolarizations in the DGC but local application of 2-AP5 to the dentate gyrus only reduced the depolarizations. The non-NMDA-receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), whether bath applied or applied locally to the DG, had little effect on the cortical events but strongly reduced the depolarizations of the DGC. The discharges induced in MEC cells by GABA-blockers were reduced by bath applied 2-AP5 but abolished by CNQX. These effects were mirrored in the dentate gyrus by a reduction in the depolarizing events by 2-AP5 and their abolition by CNQX. Local application of either antagonist to the dentate gyrus reduced but did not abolish the depolarizations. Thus, Mg+(+)-free induced events in MEC depend mainly on enhanced NMDA-receptor activity, while events induced by bicuculline are primarily dependant on non-NMDA receptors. The depolarizing events in the DGC which reflect the activity in the EC are mediated by both types of receptor, although non-NMDA receptors play a much greater role.
1. Extracellular recordings were made from slices of hippocampus plus parahippocampal regions maintained in vitro. Field potentials, recorded in the entorhinal cortex after stimulation in the subiculum, resembled those observed in vivo. 2. Washout of magnesium from the slices resulted in paroxysmal events which resembled those occurring during sustained seizures in vivo. These events were greatest in amplitude and duration in layers IV/V of the medial entorhinal cortex and could occur both spontaneously and in response to subicular stimulation. Spontaneous seizure-like events were not prevented by severing the connections between the hippocampus and entorhinal cortex, but much smaller and shorter events occurring in the dentate gyrus were stopped by this manipulation. Both spontaneous and evoked paroxysmal events were blocked by perfusion with the N-methyl-D-aspartate (NMDA) receptor antagonist, DL-2-amino-5-phosphonovalerate (2-AP5). 3. Neurons in layers IV/V were characterized by intracellular recording. Injection of depolarizing current in most cells evoked a train of nondecrementing action potentials with only weak spike frequency accommodation and little or no posttrain after hyperpolarization. 4. A small number of cells displayed burst response when depolarized by positive current. The burst consisted of a slow depolarization with superimposed action potentials which decreased in amplitude and increased in duration during the discharge. The burst was terminated by a strong after hyperpolarization and thereafter, during prolonged current pulses a train of nondecrementing spikes occurred. The burst response remained if the cell was held at hyperpolarized levels but was inactivated by holding the cell at a depolarized level. 5. Depolarizing synaptic potentials could be evoked by stimulation in the subiculum. A delayed and prolonged depolarization clearly decremented with membrane hyperpolarization and, occasionally, increased with depolarization. 6. Washout of magnesium from the slices resulted in an enhancement of the late depolarization and a reversal of its voltage dependence. Eventually a single shock to the subiculum evoked a large all-or-none paroxysmal depolarization associated with a massive increase in membrane conductance. Similar events occurred spontaneously in all cells tested. The paroxysmal depolarizations, both spontaneous and evoked, were rapidly blocked by 2-AP5. 7. It is concluded that medial entorhinal cortical cells possess several intrinsic and synaptic properties which confer an extreme susceptibility to generation of sustained seizure activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Gabapentin (1-(aminomethyl)cyclohexane acetic acid; Neurontin) is a novel anticonvulsant drug, with a mechanism of action
apparently dissimilar to that of other antiepileptic agents. We report here the isolation and characterization of a [3H]gabapentin-binding protein from pig cerebral cortex membranes. The detergent-solubilized binding protein was purified 1022-fold,
in a six-step column-chromatographic procedure, with a yield of 3.9%. The purified protein had an apparent subunit M of 130,000, and was heavily glycosylated. The partial N-terminal amino acid sequence of the M 130,000 polypeptide, EPFPSAVTIK, was identical to that reported for the α subunit of the L-type Ca channel from rabbit skeletal muscle (Hamilton, S. L., Hawkes, M. J., Brush, K., Cook, R., Chang, R. J., and Smilowitz, H.
M.(1989) Biochemistry 28, 7820-7828). High levels of [3H]gabapentin binding sites were found in membranes prepared from rat brain, heart and skeletal muscle. Binding of [3H]gabapentin to COS-7 cells transfected with α cDNA was elevated >10-fold over controls, consistent with the expression of α protein, as measured by Western blotting. Finally, purified L-type Ca channel complexes were fractionated, under dissociating conditions, on an ion-exchange column; [3H]gabapentin binding activity closely followed the elution of the α subunit. [3H]Gabapentin is the first pharmacological agent described that interacts with an α subunit of a voltage-dependent Ca channel.
1. We have compared the characteristics of spontaneous excitatory postsynaptic currents (sEPSCs) in neurons of layer IV-V and layer II of the rat entorhinal cortex (EC) using whole cell voltage-clamp recordings in a slice preparation. 2. The frequency of sEPSCs was similar in the two layers, but the events in layer IV-V had a larger mean amplitude, faster rise time, and were faster to decay. The difference in amplitude could be attributed to the presence of a population of larger events in the layer IV-V neurons that were not present in layer II. 3. Electrotonic length was greater in layer II neurons, suggesting that the difference in kinetics of the sEPSCs may be explained partly by electrotonic attenuation. 4. The frequency of sEPSCs in both layers was reduced by tetrodotoxin (TTX) to a similar extent (15-20%). However, the amplitude distribution was unchanged in layer II, whereas in layer IV-V TTX abolished most of the larger amplitude sEPSCs. 5. 6-cyano-7-nitroquinoxaline-2,3-dione or 6-nitro-7-sulphamoylbenzo (f)-quinoxaline-2,3-dione, abolished most of the sEPSCs in neurons of both layers. However, even at negative holding potentials, a population of slower time-course sEPSCs remained in the presence of these antagonists. 6. The slow sEPSCs were more frequent in layer IV-V but had similar characteristics in both layers, being increased in amplitude at more positive holding potentials or in Mg2+-free medium, and blocked by 2-amino-5-phosphonovalerate (AP5). 7. AP5 alone (i.e., without addition of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonists) reduced the peak amplitude and decay phase of sEPSCs in layer IV-V neurons but appeared to have little effect on amplitude and only a weak effect on decay phase in layer II. 8. Thus both layer IV-V and layer II neurons of the EC suffer continuous spontaneous excitation. However, layer IV-V neurons exhibit larger amplitude sEPSCs, probably mediated by release of multiple quanta of neurotransmitter. In addition, although both types of neurons display spontaneous excitation mediated by N-methyl-D-aspartate receptors, this component appears more pronounced in the deeper layers.
Sequence database searches with the alpha2delta subunit as probe led to the identification of two new genes encoding proteins with the essential properties of this calcium channel subunit. Primary structure comparisons revealed that the novel alpha2delta-2 and alpha2delta-3 subunits share 55.6 and 30.3% identity with the alpha2delta-1 subunit, respectively. The number of putative glycosylation sites and cysteine residues, hydropathicity profiles, and electrophysiological character of the alpha2delta-3 subunit indicates that these proteins are functional calcium channel subunits. Coexpression of alpha2delta-3 with alpha1C and cardiac beta2a or alpha1E and beta3 subunits shifted the voltage dependence of channel activation and inactivation in a hyperpolarizing direction and accelerated the kinetics of current inactivation. The kinetics of current activation were altered only when alpha2delta-1 or alpha2delta-3 was expressed with alpha1C. The effects of alpha2delta-3 on alpha1C but not alpha1E are indistinguishable from the effects of alpha2delta-1. Using Northern blot analysis, it was shown that alpha2delta-3 is expressed exclusively in brain, whereas alpha2delta-2 is found in several tissues. In situ hybridization of mouse brain sections showed mRNA expression of alpha2delta-1 and alpha2delta-3 in the hippocampus, cerebellum, and cortex, with alpha2delta-1 strongly detected in the olfactory bulb and alpha2delta-3 in the caudate putamen.
In the present study we tested the effects of the antihyperalgesic compound gabapentin on dorsal horn neurones in adult spinal cord. Slices were taken from control and hyperalgesic animals suffering from streptozocin-induced diabetic neuropathy. At concentrations up to 100 μM, bath application failed to affect the resting membrane properties of dorsal horn neurones taken from both groups of animal. In contrast, bath application of gabapentin dramatically reduced the magnitude of the excitatory postsynaptic current (EPSC) in neurones taken from hyperalgesic animals without altering the magnitude of the EPSC in control animals. Using a paired pulse stimulation protocol, together with analysis of miniature EPSC's, it was possible to demonstrate that gabapentin mediated these effects via a pre-synaptic site of action.
British Journal of Pharmacology (2000) 130, 1731–1734; doi:10.1038/sj.bjp.0703530
It has been suggested that the anticonvulsant effect of lamotrigine resides with it's ability to block voltage gated Na-channels at presynaptic sites, thus stabilizing the presynapse, and, consequently, reducing the release of synaptic transmitters. Neurochemical studies have shown that it can inhibit the veratrine-stimulated release of the excitatory transmitter, glutamate from cortical tissue, but that at slightly higher concentrations it also reduces the release of the inhibitory transmitter, GABA. In the present study we examined the effect of the drug on the release of these transmitters at synapses in the rat entorhinal cortex, using the whole-cell patch clamp technique to record spontaneous excitatory (EPSCs) and inhibitory postsynaptic currents (IPSCs). Lamotrigine reduced the frequency, but not the amplitude of spontaneous EPSCs. This clearly indicated a presynaptic effect to reduce the release of glutamate. However, the same effect was observed when we tested the drug on miniature EPSCs, recorded in the presence of TTX and Cd, showing that blockade of Na-channels or Ca-channels was not a prerequisite for inhibition of glutamate release. In contrast to it's effects on EPSCs, lamotrigine increased both the frequency and amplitude of spontaneous IPSCs, suggesting that the drug was acting presynaptically to enhance GABA release. Again, similar effects were seen with miniature IPSCs recorded in TTX. These opposite effects of lamotrigine on glutamate and GABA release are similar to those we have reported previously with phenytoin, and suggest that reciprocal modulation of the background release of the major excitatory and inhibitory transmitters may be a significant factor in dampening excitability in pathologically hyperexcitable cortical networks.
The cellular mechanisms responsible for large miniature currents in some brain synapses remain undefined. In Purkinje cells, we found that large-amplitude miniature inhibitory postsynaptic currents (mIPSCs) were inhibited by ryanodine or by long-term removal of extracellular Ca2+. Two-photon Ca2+ imaging revealed random, ryanodine-sensitive intracellular Ca2+ transients, spatially constrained at putative presynaptic terminals. At high concentration, ryanodine decreased action-potential-evoked rises in intracellular Ca2+. Immuno-localization showed ryanodine receptors in these terminals. Our data suggest that large mIPSCs are multivesicular events regulated by Ca2+ release from ryanodine-sensitive presynaptic Ca2+ stores.
The human brain voltage-gated Na+ channel type IIA alpha subunit was cloned and stably expressed in Chinese hamster ovary cells and its biophysical and pharmacological properties were studied using whole-cell voltage-clamp. Fast, transient inward currents of up to -8,000 pA were elicited by membrane depolarization of the recombinant cells. Channels activated at -50 mV and reached maximal activation at -10 mV to 0 mV. The reversal potential was 62 +/- 2 mV which is close to the Na+ equilibrium potential. The half-maximal activation and inactivation voltages were -24 +/- 2 mV and -63 +/- 1 mV, respectively. Currents were reversibly blocked by tetrodotoxin with a half-maximal inhibition of 13 nM. The effects of four commonly used anti-convulsant drugs were examined for the first time on the cloned human type IIA channel. Lamotrigine and phenytoin produced concentration- and voltage-dependent inhibition of the type IIA currents, whereas, sodium valproate and gabapentin (up to 1 mM) had no effect. These results indicate that recombinant human type IIA Na+ channels conduct tetrodotoxin-sensitive Na+ currents with similar properties to those observed in recombinant rat brain type IIA and native rat brain Na+ channels. This stable cell line should provide a useful tool for more detailed characterization of therapeutic modulators of human Na+ channels.
Sequence database searches with the alpha(2)delta subunit as probe led to the identification of two new genes encoding proteins with the essential properties of this calcium channel subunit. Primary structure comparisons revealed that the novel alpha(2)delta-2 and alpha(2)delta-3 subunits share 55.6 and 30.3% identity with the alpha(2)delta-1 subunit, respectively. The number of putative glycosylation sites and cysteine residues, hydropathicity profiles, and electrophysiological character of the alpha(2)delta-3 subunit indicates that these proteins are functional calcium channel subunits. Coexpression of alpha(2)delta-3 with alpha(1C) and cardiac beta 2a or alpha(1E) and beta 3 subunits shifted the voltage dependence of channel activation and inactivation in a hyperpolarizing direction and accelerated the kinetics of current inactivation. The kinetics of current activation were altered only when alpha(2)delta-1 or alpha(2)delta-3 was expressed with alpha(1C). The effects of alpha(2)delta-3 on alpha(1C) but not alpha(1E) are indistinguishable from the effects of alpha(2)delta-1. Using Northern blot analysis, it was shown that alpha(2)delta-3 is expressed exclusively in brain, whereas alpha(2)delta-2 is found in several tissues. In situ hybridization of mouse brain sections showed mRNA expression of alpha(2)delta-1 and alpha(2)delta-3 in the hippocampus, cerebellum, and cortex, with alpha(2)delta-1 strongly detected in the olfactory bulb and alpha(2)delta-3 in the caudate putamen.
High-voltage activated calcium channels are modulated by a series of auxiliary proteins, including those of the α2δ family. Until recently, only a single α2δ subunit was known, but two further members, α2δ-2 and -3, have since been identified. In this study, the structure of these two novel subunits has been characterized and binding of the antiepileptic drug gabapentin investigated. Using antibodies directed against the amino terminal portion of the proteins, the gross structure of the subunits could be analyzed by Western blotting. Similar to α2δ-1, both α2δ-2 and -3 subunits consist of two proteins—a larger α2 and a smaller δ that can be separated by reduction. The subunits are also highly N -glycosylated with approximately 30 kDa of their mass consisting of oligosaccharides. α2δ-1 was detected in all mouse tissues studied, whereas α2δ-2 was found at high levels in brain and heart. The α2δ-3 subunit was observed only in brain. α2δ-1 and α2δ-2, but not α2δ-3, were found to bind gabapentin. The K d value of gabapentin binding to α2δ-2 was 153 nM compared with the higher affinity binding to α2δ-1 ( K d = 59 nM).
: The system L transporter is generally considered to be one of the major Na+-independent carriers for large neutral α-amino acids in mammalian cells. However, we found that cultured astrocytes from rat brain cortex accumulate gabapentin, a γ-amino acid, predominantly by this α-amino acid transport system. Uptake of gabapentin by system L transporter was also examined in synaptosomes and Chinese hamster ovary (CHO) cells. The inhibition pattern displayed by various amino acids on gabapentin uptake in astrocytes and synaptosomes corresponds closely to that observed for the system L transport activity in CHO cells. Gabapentin and leucine have Km values that equal their Ki values for inhibition of each other, suggesting that leucine and gabapentin compete for the same system L transporter. By contrast, gabapentin exhibited no effect on uptake of GABA, glutamate, and arginine, indicating that these latter three types of brain transporters do not serve for uptake of gabapentin. A comparison of computer modeling analysis of gabapentin and l-leucine structures shows that although the former is a γ-amino acid, it can assume a conformation that can resemble the L-form of a large neutral α-amino acid such as l-leucine. The steady-state kinetic study in astrocytes and CHO cells indicates that the intracellular concentrations of gabapentin are about two to four times higher than that of leucine. The uptake levels of these two substrates are inversely related to their relative exodus rates. The concentrating ability by system L observed in astrocytes is consistent with the substantially high accumulation gradient of gabapentin in the brain tissue as determined by microdialysis.
Experimental studies suggest important interactions between hippocampus and entorhinal cerebral cortex in generation of temporal lobe seizure activity. We studied electrical expression of spontaneous temporallobe ictal activity in hippocampus and entorhinal cortex in 9 medically refractory epileptic patients who had intracranial depth and subdural electrodes implanted during surgical evaluation. All 9 patients subsequently under-went anteromedial temporal lobectomy with hippocam-pectomy, all had >50% decrease in neuronal cell density in hippocampal CA1 and CA3, and all had good to excellent seizure outcome after operation. Two to 10 spontaneous seizures were analyzed per patient (total 41 seizures). Nine patients had variable onset of seizure activity recorded in hippocampus, entorhinal cortex, or both simultaneously. Low-voltage fast activity was observed in either location and varied among seizures in an individual patient. Periodic preictal spikes, when present, were often synchronous in both locations, but were noted independently only in hippocampus. Our data suggest that preictal spikes and low-voltage fast seizure discharges have anatomically distinct origins, and that some syndromes of medial temporal lobe epilepsy involve interactions between entorhinal and hippocampal regions that act together to produce and propagate the seizures in such patients.
Clinically available antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium (Na) channels, -y-aminobutyric acidA (GABAA) receptors, or calcium (Ca) channels. Benzodiazepines and barbiturates enhance GABAA-receptor-mediated inhibition. Phenytoin, car-bamazepine and, possibly, valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing Na channel inactivation. Ethosuximide and VPA reduce a low threshold (T-type) Ca-channel current. The mechanisms of action of recently developed AEDs are less clear. Lamotrigine may decrease sustained high-frequency repetitive firing of voltage-dependent Na action potentials, and gabapentin (GBP) appears to bind to a specific binding site in the CNS with a restricted regional distribution. However, the identity of the binding site and the mechanism of action of GBP remain uncertain. The antiepileptic effect of felbamate may involve interaction at the strychnine-insensitive glycine site of the Af-methyl-D-aspartate receptor, but the mechanism of action is not yet proven.
Effects of phenytoin (PHT) on the intracellular calcium reservoir, lysosome-like granules (LLG), and calcium-related intracellular events during pentylenetetrazole (PTZ)-induced bursting activity in the neurons of the Japanese land snail,Euhadra peliomphala, were examined. PTZ-induced morphological changes of LLG was inhibited by PHT. Calcium release from LLG was inhibited by PHT. PHT also inhibited the cyclic AMP increase by PTZ. PHT inhibited the increase in calcium-dependent protein kinase activity during PTZ-induced bursting activity. These findings suggest that PHT inhibits, as a first step, cyclic AMP increase which is one of the trigger factors of bursting activity as well as subsequent calcium-related intracellular pathological changes during seizure activity.
Gabapentin (1(aminomethyl) cyclohexane acetic acid; GBP) is a recently developed anticonvulsant, for which the mechanism of action remains quite elusive. Besides its possible interaction with glutamate synthesis and/or GABA release, in cerebral membranes gabapentin has been shown to bind directly to the α2δ subunit of the calcium channel. Therefore, we have tested the possibility that gabapentin affects high threshold calcium currents in central neurons. Calcium currents were recorded in whole-cell patch-clamp mode in neurons isolated from neocortex, striatum and external globus pallidus of the adult rat brain. A large inhibition of calcium currents by gabapentin was observed in pyramidal neocortical cells (up to 34%). Significantly, the gabapentin-mediated inhibition of calcium currents saturated at particularly low concentrations (around 10 μM), at least in neocortical neurons (IC50 about 4 μM). A less significant inhibition was seen in medium spiny neurons isolated from striatum (−12.4%) and in large globus pallidus cells (−10.4%). In all these areas, however, the GBP-induced block was fast and largely voltage-independent. Dihydropyridines (nimodipine, nifedipine) prevented the gabapentin response. ω-conotoxin GVIA and ω-conotoxin MVIIC, known to interfere with the currents driven by α1b and α1a calcium channels, did not prevent but partially reduced the response. These findings imply that voltage-gated calcium channels, predominately the L-type channel, are a direct target of gabapentin and may support its use in different clinical conditions, in which intracellular calcium accumulation plays a central role in neuronal excitability and the development of cellular damage.
We have combined recordings with extracellular microelectrodes or ion-sensitive electrodes and imaging of intrinsic optical signal changes to study the spatiotemporal pattern of seizure onset and spread during development. We have employed the entorhinal cortex–hippocampus brain slice preparation of juvenile rats at different stages of postnatal maturation. Three age groups were analyzed: 4–6 days (age group I), 10–14 days (age group II), and 20–23 days (age group III). Seizure-like events were induced by perfusion of slices with Mg2+-free artificial cerebrospinal fluid thereby removing the Mg2+ block of the N-methyl--aspartate receptor. Seizure susceptibility was highest in age groups II and III. In age group I seizure-like events originated mainly in the hippocampus proper. Seizure-like events in age group II originated mainly in the entorhinal cortex and this tendency was even more pronounced in age group III. Invasion of the hippocampal formation via the perforant path–dentate gyrus and via the subiculum was seen in age groups I and II. In contrast, in age group III the hippocampus was invaded exclusively via the subiculum pathway. The velocity of spread at which seizure-like events propagated within different regions of the slice increased with postnatal age. The characteristics of onset, spread patterns, and propagation velocities as revealed by this study allow insight into the evolving properties of the developing brain.
Although the cellular mechanisms of pharmacological actions of gabapentin (Neurontin) remain incompletely described, several hypotheses have been proposed. It is possible that different mechanisms account for anticonvulsant, antinociceptive, anxiolytic and neuroprotective activity in animal models. Gabapentin is an amino acid, with a mechanism that differs from those of other anticonvulsant drugs such as phenytoin, carbamazepine or valproate. Radiotracer studies with [14C]gabapentin suggest that gabapentin is rapidly accessible to brain cell cytosol. Several hypotheses of cellular mechanisms have been proposed to explain the pharmacology of gabapentin: 1. Gabapentin crosses several membrane barriers in the body via a specific amino acid transporter (system L) and competes with leucine, isoleucine, valine and phenylalanine for transport. 2. Gabapentin increases the concentration and probably the rate of synthesis of GABA in brain, which may enhance non-vesicular GABA release during seizures. 3. Gabapentin binds with high affinity to a novel binding site in brain tissues that is associated with an auxiliary subunit of voltage-sensitive Ca2+ channels. Recent electrophysiology results suggest that gabapentin may modulate certain types of Ca2+ current. 4. Gabapentin reduces the release of several monoamine neurotransmitters. 5. Electrophysiology suggests that gabapentin inhibits voltage-activated Na+ channels, but other results contradict these findings. 6. Gabapentin increases serotonin concentrations in human whole blood, which may be relevant to neurobehavioral actions. 7. Gabapentin prevents neuronal death in several models including those designed to mimic amyotrophic lateral sclerosis (ALS). This may occur by inhibition of glutamate synthesis by branched-chain amino acid aminotransferase (BCAA-t).
Presynaptic inhibition of neurotransmitter release is thought to be mediated by a reduction of axon terminal Ca2+ current. We have compared the actions of several known inhibitors of evoked glutamate release with the actions of the Ca2+ channel antagonist Cd2+ on action potential-independent synaptic currents recorded from CA3 neurons in hippocampal slice cultures. Baclofen and adenosine decreased the frequency of miniature excitatory postsynaptic currents (mEPSCs) without affecting the distribution of their amplitudes. Cd2+ blocked evoked synaptic transmission, but had no effect on the frequency or amplitude of either mEPSCs or inhibitory postsynaptic currents (IPSCs). Inhibition of presynaptic Ca2+ current therefore appears not to be required for the inhibition of glutamate release by adenosine and baclofen. Baclofen had no effect on the frequency of miniature IPSCs, indicating that gamma-aminobutyric acid B-type receptors exert distinct presynaptic actions at excitatory and inhibitory synapses.
Gabapentin (GBP) is a neutral amino acid and a GABA analog which in animal experimental models has shown a broad anticonvulsant spectrum. To evaluate the penetration of GBP into the CSF in humans as well as its possible effects on free and total GABA, homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), a special investigation was performed as part of a placebo controlled add-on study of GBP in partial epilepsy. At the end of the 3-month double-blind period, 5 patients on placebo were given a single oral dose of GBP. Four patients received 600 mg and 1 patient 1200 mg GBP. CSF was collected immediately before and at 6, 24 and 72 h after the single dose. 5 ml of plasma was collected at 1, 2, 3, 6, 12, 24, 48 and 72 h. Plasma concentrations and plasma elimination half-life (4-6 h) of GBP were in agreement with the results of previous studies. The CSF/plasma concentration ratio of GBP 6 h after drug was 0.1. After 24 h, GBP could only be recovered in the CSF of the patient given 1200 mg. The CSF/plasma ratio at that time was 0.3. Free and total GABA concentrations did not change, but CSF 5-HIAA and HVA increased at 24 and 72 h post dose. The CSF/plasma ratio of gabapentin is similar to that of other amino acids.
Of 204 patients who underwent a selective amygdalohippocampectomy at our hospital, we studied 30 in whom special pre- and postoperative MR imaging was carried out and who were followed up for at least 1 year postoperatively. We measured the total size of the resection and the extent to which the following specific mediobasal temporal lobe structures had been removed: amygdala, hippocampus, pes hippocampi, dentate gyrus, parahippocampal gyrus, uncus and subiculum. Postoperative seizure control was correlated with the overall size of the resection as well as with the resection scores of the above mentioned limbic subcompartments. The mean size of the removed tissue was 7.2 cm3 (range: 2.1-17.7). The mean resection scores of the limbic subcompartments (in percentages) are: amygdala 92%, hippocampus 46%, pes hippocampi 92%, dentate gyrus 45%, parahippocampal gyrus 32%, uncus 92%, subiculum 40%. Although a small resection did not exclude a good outcome, the general tendency was that a better outcome was obtained from a larger resection. With regard to the resection scores of the limbic subcompartments, a positive correlation emerged between good postoperative outcome and the radicality of the removal of the parahippocampal gyrus (and the subiculum, which has been evaluated separately). These findings support our previously formulated amplifier hypothesis for the parahippocampal gyrus.
Effects of phenytoin (PHT) on the intracellular calcium and intracellular protein changes during pentylenetetrazole (PTZ)-induced bursting activity in the neurons of the Japanese land snail Euhadra peliomphala were examined. In the examination with a computer controlled electron probe X-ray microanalyzer, PHT clearly inhibited the intracellular calcium shift induced by PTZ as well as the calcium binding state change near the cell membrane. PHT also clearly inhibited the intracellular protein changes induced by PTZ. PHT, however, did not show any change in the transmembrane ionic currents such as the sodium current, calcium current and potassium current. These findings suggest that one of the main sites of anticonvulsant action of PHT is pathologically changed intracellular calcium movement and intracellular protein changes during seizure discharge.
The electrophysiological properties of the neural pathways between the hippocampus and the entorhinal cortex were studied intraoperatively in 31 patients undergoing anterior temporal lobectomy for medically intractable complex partial seizures. The hippocampus, removed en bloc, was studied histologically and the pathology was correlated with the electrophysiological findings. In 29 of the patients, entorhinal stimulation evoked a characteristic positive-negative potential in the hippocampus. The entorhinal-evoked hippocampal response closely resembled, or was identical to, the spontaneously occurring hippocampal interictal spike discharge. In patients with Ammon's horn sclerosis in whom there was a major loss of neurons in the hippocampal subfields CA1, CA3, and CA4, the evoked responses were of simple morphology and long latency (mean 21.9 msec to the peak of the first potential). In patients with a ganglioglioma in whom the hippocampus was histologically normal, the evoked responses were of greater complexity and shorter latency (mean 11.8 msec). Stimulation at a single entorhinal site evoked similar waveforms at different hippocampal recording sites. Conversely, stimulation at different entorhinal sites evoked similar responses at a single hippocampal recording site. Stimulation of the hippocampus evoked a potential in the entorhinal cortex and, in some instances, in the amygdala, insula, and lateral temporal cortex. These connections may produce a positive feedback loop that favors seizure generation.
The synapse is a major regulatory site that has been implicated in modulating neuronal excitability and seizure discharge. Voltage-dependent calcium (Ca2+) entry at the synapse plays a major role in initiating neurotransmitter release and in regulating synaptic function. Thus, obtaining a molecular understanding of the effects of Ca2+ on synaptic modulation would provide important insights into the regulation of synaptic activity and, possibly, the biochemical basis for some forms of epilepsy. Calmodulin is a major Ca2+-binding protein in brain that has been implicated in mediating many of the second messenger effects of Ca2+ on neuronal function. The evidence implicating calmodulin in modulating synaptic excitability will be presented. Calmodulin was shown to be present at the synapse in association with synaptic vesicles and in the postsynaptic density. In addition, several calmodulin-regulated synaptic biochemical processes have been identified, including Ca2+- and calmodulin-regulated protein phosphorylation, vesicular neurotransmitter release, vesicle-membrane interactions, and neurotransmitter turnover. These results indicate that calmodulin may play an important role in synaptic modulation and provide a molecular approach to investigating the Ca2+ signal in brain. Several anticonvulsants have been shown to regulate some of calcium's effects on neuronal function. These anticonvulsants include phenytoin, carbamazepine, and the benzodiazepines. All of these compounds are effective against maximal electric shock (MES) seizure models in animals. Anticonvulsants were tested on several of the Ca2+-calmodulin-regulated synaptic biochemical systems. The results demonstrate that phenytoin, carbamazepine, and the benzodiazepines were effective in inhibiting calcium calmodulin protein kinase activity in membrane and purified kinase preparations, vesicle neurotransmitter release, vesicle-membrane interactions, and voltage-sensitive calcium uptake in intact synaptosomes. Phenobarbital, ethosuximide, trimethadione, valproic acid, and vinyl gamma-aminobutyric acid (GABA) were not effective in inhibiting these calcium-regulated processes. Thus, the effects of anticonvulsants on calcium-regulated processes were selective to a group of anticonvulsants that had been shown in several electrophysiological systems to antagonize some of the actions of calcium on neuronal excitability. These observations suggested the existence of specific membrane receptors that might mediate the effects of these anticonvulsants on neuronal function through the regulation of calcium-calmodulin-regulated processes.(ABSTRACT TRUNCATED AT 400 WORDS)
Superfused rat brain cortex slices preincubated with 3H-noradrenaline or 3H-serotonin and superfused rabbit caudate nucleus slices preincubated with 3H-choline were used to examine the effects of gabapentin (an amino acid chemically related to gamma-aminobutyric acid, GABA) on the electrically evoked 3H overflow. Gabapentin inhibited the electrically (3 Hz) evoked 3H overflow from slices preincubated with the 3H-monoamines in a concentration-dependent manner (at 1 mmol/l by 20-30%), but did not affect the evoked overflow from slices preincubated with 3H-choline. The following drugs did not modify the inhibitory effects of gabapentin: bicuculline, RS-baclofen, GABA, phentolamine, metitepin, cocaine, and the inhibitor of serotonin uptake, 6-nitroquipazine. Gabapentin did not modify the inhibitory effect of GABA on the evoked 3H overflow from slices preincubated with 3H-serotonin. In slices preincubated with 3H-noradrenaline the inhibitory effect of gabapentin was still observed when the stimulation frequency was 10 instead of 3 Hz. In conclusion, gabapentin mimics GABAB receptor activation, but it appears to act by a GABA receptor-independent, as yet unidentified mechanism.
Kainic acid, bicuculline or pentetrazole have been injected systemically in rats. Clinical, electrographic and metabolic alterations (using the deoxyglucose method), have been studied in relation to subsequently demonstrated neuropathology using stains for degenerating nerve fibers or neurons. Twenty minutes after administration of the toxin (9–12 mg/kg i.p.), the animals displayed ‘wet shakes’; their frequency of occurrence was steadily increased before subsiding 60 min later when the overt typical limbic motor seizures started. The latter progressively evolved into status epilepticus. Epileptiform activity started (approximately 20 min after the injections) in the temporal pole of the hippocampal formation (in particular the entorhinal cortex) and propagated to the rostral Ammon's horn, the amygdala, medial thalamus and pre-frontal cortex and diffusely to the cortical electroencephalogram. Postictal depressions were exclusively seen in the hippocampal formation, thus further stressing the central position occupied by this structure in the electrographic effects of the toxin. At longer delays (3–6 days), rhythmic spikes were exclusively present in the amygdaloid complex.
Gabapentin (GBP) is a cyclic gamma-aminobutyric acid (GABA) analog and investigational antiepileptic drug which is effective in the treatment of a variety of human and experimental seizures. GBP's antiepileptic mechanism of action is not known. The present studies tested for effects of GBP on inhibitory (GABA and glycine) and excitatory (N-methyl-D-aspartate (NMDA) and non-NMDA) amino acid neurotransmitter receptors, on repetitive firing of sodium (Na+) action potentials, and on voltage-dependent calcium (Ca2+) channel currents in cultured rodent neurons using intracellular, whole cell, or single channel recording techniques. GBP did not have a significant effect in any experiment when tested at or above concentrations that are therapeutic in humans except for a variable enhancement of NMDA-evoked depolarizations. These results suggest that the antiepileptic activity of GBP is not due to direct effects at receptors for inhibitory or excitatory amino acids or on voltage-dependent Na+ or Ca2+ channels.
Clinically available antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium (Na) channels, gamma-aminobutyric acid A (GABAA) receptors, or calcium (Ca) channels. Benzodiazepines and barbiturates enhance GABAA-receptor-mediated inhibition. Phenytoin, carbamazepine and, possibly, valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing Na channel inactivation. Ethosuximide and VPA reduce a low threshold (T-type) Ca-channel current. The mechanisms of action of recently developed AEDs are less clear. Lamotrigine may decrease sustained high-frequency repetitive firing of voltage-dependent Na action potentials, and gabapentin (GBP) appears to bind to a specific binding site in the CNS with a restricted regional distribution. However, the identity of the binding site and the mechanism of action of GBP remain uncertain. The antiepileptic effect of felbamate may involve interaction at the strychnine-insensitive glycine site of the N-methyl-D-aspartate receptor, but the mechanism of action is not yet proven.
The system L transporter is generally considered to be one of the major Na(+)-independent carriers for large neutral alpha-amino acids in mammalian cells. However, we found that cultured astrocytes from rat brain cortex accumulate gabapentin, a gamma-amino acid, predominately by this alpha-amino acid transport system. Uptake of gabapentin by system L transporter was also examined in synaptosomes and Chinese hamster ovary (CHO) cells. The inhibition pattern displayed by various amino acids on gabapentin uptake in astrocytes and synaptosomes corresponds closely to that observed for the system L transport activity in CHO cells. Gabapentin and leucine have Km values that equal their Ki values for inhibition of each other, suggesting that leucine and gabapentin compete for the same system L transporter. By contrast, gabapentin exhibited no effect on uptake of GABA, glutamate, and arginine, indicating that these latter three types of brain transporters do not serve for uptake of gabapentin. A comparison of computer modeling analysis of gabapentin and L-leucine structures shows that although the former is a gamma-amino acid, it can assume a conformation that can resemble the L-form of a large neutral alpha-amino acid such as L-leucine. The steady-state kinetic study in astrocytes and CHO cells indicates that the intracellular concentrations of gabapentin are about two to four times higher than that of leucine. The uptake levels of these two substrates are inversely related to their relative exodus rates. The concentrating ability by system L observed in astrocytes is consistent with the substantially high accumulation gradient of gabapentin in the brain tissue as determined by microdialysis.
After years without any major breakthroughs in the treatment of epilepsy disorders, a new wave of antiepileptic drugs have become available to clinicians. Felbamate, gabapentin, lamotrigine and vigabatrin are among the most promising of this new generation of drugs and, when used as add-on therapy, provide some improvement in a significant number of patients suffering from previously refractory epilepsy whilst exhibiting a lower risk of unwanted side-effects than traditional antiepileptic drugs. In this article, Neil Upton reviews the recent discoveries that suggest these four new agents exert their antiepileptic properties by acting through diverse and often novel mechanisms, some of which are by design, and some of which are by chance. Also highlighted are examples of the most innovative mechanistic approaches currently being adopted to produce the next generation of antiepileptic drugs.
The ability of large neutral amino acids to interact with a site in mouse and pig brain labelled by [3H]gabapentin was examined. As previously described for rat tissue, [3H]gabapentin bound to synaptic plasma membranes prepared from mouse or pig cerebral cortex with high affinity (Kinetically derived KD = 14 and 17 nM for mouse and pig, respectively). Equilibrium binding in each species was inhibited by gabapentin and a range of large neutral amino acids. L-leucine (IC50 = 80 nM), L-isoleucine (IC50 = 72 nM), L-norleucine (IC50 = 40 nM) and L-methionine (IC50 = 50 nM) were the most potent of those tested. Binding was also inhibited by L-phenylalanine (IC50 = 380 nM), L-valine (IC50 = 310 nM) and the selective system-L substrate 2-amino-2-carboxy-bicycloheptane (IC50 = 420 nM) but not by the sodium-dependent System-A substrate methylaminoisobutyric acid. The presence of a submaximal concentration of leucine reduced [3H]gabapentin binding affinity but did not affect the maximum number of binding sites, suggesting a competitive interaction between leucine and the binding protein. The results suggest [3H]gabapentin may label a site in brain that resembles the large neutral amino acid transporter described in other tissues.
3-Isobutyl GABA is a derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and is also structurally related to the novel anticonvulsant gabapentin. The S(+) enantiomer of 3-isobutyl GABA blocks maximal electroshock seizures in mice and also potently displaces tritiated gabapentin from a novel high-affinity binding site in rat brain membrane fractions. The R(-) enantiomer is much less active in both assays, suggesting that the gabapentin binding site is involved in the anticonvulsant activity of 3-isobutyl GABA.
The binding characteristics of [3H]gabapentin, the radiolabelled analogue of the novel anticonvulsant gabapentin (1-(aminomethyl)cyclohexaneacetic acid) were studied using purified synaptic plasma membranes prepared from rat cerebral cortex. In 10 mM HEPES buffer [3H]gabapentin bound to a single population of sites with high affinity (KD = 38 +/- 2.8 nM) with a maximum binding capacity of 4.6 +/- 0.4 pmol/mg protein, reaching equilibrium after 30 min at 20 degrees C. This novel site was unique to the central nervous system with little or no specific [3H]gabapentin being measurable in a range of peripheral tissues. Binding was potently inhibited by a range of gabapentin analogues and 3-alkyl substituted gamma-aminobutyric acid (GABA) derivates although GABA itself and the selective GABAB receptor ligand baclofen, were only weakly active. Gabapentin itself (IC50 = 80 nM) and 3-isobutyl GABA (IC50 = 80 nM) which also has anticonvulsant properties, showed the highest affinity for the binding site. Of a wide range of other pharmacologically active compounds only the polyamines spermine and spermidine influenced [3H]gabapentin binding, with both compounds producing a maximum of 50% inhibition of specific binding. Magnesium ions produced a similar pattern of inhibition but the effect of the polyamines and magnesium ions were not additive. The data provide evidence for the existence in brain of a novel binding site that may mediate the anticonvulsant effects of gabapentin and other potential anticonvulsant compounds.
Gabapentin (1-(aminomethyl)cyclohexaneacetic acid) is a neuroprotective agent with antiepileptic properties. The structure is small (molecular weight less than 200), is zwitterionic, and resembles an amino acid with the exception that it does not contain a chiral carbon and the amino group is not alpha to the carboxylate functionality. Gabapentin is not metabolized by humans, and thus, the amount of gabapentin excreted by the renal route represents the fraction of dose absorbed. Clinical trials have reported dose-dependent bioavailabilities ranging from 73.8 +/- 18.3 to 35.7 +/- 18.3% when the dose was increased from 100 to 1600 mg. The permeability of gabapentin in the rat intestinal perfusion system was consistent with carrier-mediated absorption, i.e., a 75 to 80% decrease in permeability when the drug concentration was increased from 0.01 to 50 mM (0.46 +/- 0.05 to 0.12 +/- 0.04). Excellent agreement was obtained between the actual clinical values and the predicted values from in situ results for the fraction of dose absorbed calculated using the theoretically derived correlation, Fabs = 1 - exp(-2Peff) by Amidon et al. (Pharm. Res. 5:651-654, 1988). The permeability values obtained for gabapentin correspond to 67.4 and 30.2% of the dose absorbed at the low and high concentrations, respectively. In the everted rat intestinal ring system, gabapentin shared an inhibition profile similar to that of L-phenylalanine. Characteristics of gabapentin uptake included cross-inhibition with L-Phe, sensitivity to inhibition by L-Leu, stereoselectivity as evidenced by incomplete inhibition by D-Phe, and lack of effect by Gly.(ABSTRACT TRUNCATED AT 250 WORDS)
Activation of either muscarinic cholinergic or metabotropic glutamatergic presynaptic receptors inhibits evoked excitatory synaptic responses in the hippocampus. We have investigated two possible mechanisms underlying these actions using whole-cell recording from CA3 pyramidal cells in hippocampal slice cultures. Application of either methacholine (MCh, 10 microM) or trans-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD, 10 microM) was found to reduce the frequency of miniature excitatory postsynaptic currents (mEPSCs) by roughly 50%, without changing their mean amplitude. The voltage-dependent Ca2+ channel blocker Cd2+ (100 microM), in contrast, had no effect on the mEPSC frequency. When the extracellular [K+] was increased from 2.7 to 16 mM, the mEPSC frequency increased from 1.7 to 4.9 Hz. This increase could be completely reversed by applying Cd2+, indicating that it was triggered by voltage-dependent Ca2+ influx. MCh and t-ACPD each decreased the mEPSC frequency by roughly 50% under these conditions. Because the agonists were equally effective in inhibiting spontaneous release whether voltage-dependent channels were activated or not, we conclude that presynaptic cholinergic and glutamatergic inhibition is not mediated by inhibition of presynaptic Ca2+ channels, but rather by a direct interference in the neurotransmitter release process at some point subsequent to Ca2+ influx.
1. Gabapentin is a novel anticonvulsant with an unknown mechanism of action. Recent homogenate binding studies with [3H]-gabapentin have suggested a structure-activity relationship similar to that shown for the amino acid transport system responsible for the uptake of large neutral amino acids (LNAA). 2. The autoradiographic binding distribution of [3H]-gabapentin in rat brain was compared with the distributions for excitatory amino acid receptor subtypes and the uptake sites for excitatory and large neutral amino acids in consecutive rat brain sections. 3. Densitometric measurement of the autoradiographic images followed by normalisation with respect to the hippocampus CA1 stratum radiatum, was carried out before comparison of each binding distribution with that of [3H]-gabapentin by linear regression analysis. The correlation coefficients observed showed no absolute correlation was observed between the binding distributions of [3H]-gabapentin and those of the excitatory amino acid receptor subtypes. The acidic and large neutral amino acid uptake site distributions demonstrated a much closer correlation to the [3H]-gabapentin binding site distribution. The correlation coefficients for D-[3H]-aspartate, L-[3H]-leucine and L-[3H]-isoleucine binding site distributions were 0.76, 0.90 and 0.88 respectively. 4. Concentration-dependent inhibition by unlabelled gabapentin of autoradiographic binding of L-[3H]-leucine and L-[3H]-isoleucine was observed, with non-specific binding levels being reached at concentrations between 10 and 100 microM. 5. Excitotoxic quinolinic acid lesion studies in rat brain caudate putamen and autoradiography were carried out for the amino acid uptake sites mentioned above. The resulting glial infiltration of the lesioned areas was visualized by autoradiography using the peripheral benzodiazepine receptor specific ligand [3H]-PK11195. A significant decrease in binding density in the lesioned area compared with sham-operated animals was observed for D-[3H]-aspartate, L-[3H]-leucine, L-[3H]-isoleucine and [3H]-gabapentin, whilst [3H]-PK11195 showed a significant increase in binding density indicative of glial infiltration into the lesioned area. These results suggest that the gabapentin binding site and the acidic and LNAA uptake site may be present on cell bodies of a neuronal population of cells. 6. From these studies it appears that [3H]-gabapentin, L-[3H]-leucine and L-[3H]-isoleucine bind to the same site in rat brain. The inhibition of [3H]-gabapentin binding by the LNAA uptake system-specific ligand, BCH, suggests that [3H]-gabapentin may label this uptake site, termed system-L. Conversely these ligands could be labelling a novel site that coincidentally has a similar structure-activity relationship to this uptake site. These results suggest a novel mechanistically relevant site of action for gabapentin and may enable further anti-epileptic agents of this type to be developed.