[Show abstract][Hide abstract] ABSTRACT: Antipsychotics may cause tardive dyskinesia in humans and orofacial dyskinesia in rodents. Although the dopaminergic system has been implicated in these movement disorders, which involve the basal ganglia, their underlying pathomechanisms remain unclear. CB1 cannabinoid receptors are highly expressed in the basal ganglia, and a potential role for endocannabinoids in the control of basal ganglia-related movement disorders has been proposed. Therefore, this study investigated whether CB1 receptors are involved in haloperidol-induced orofacial dyskinesia in rats. Adult male rats were treated for four weeks with haloperidol decanoate (38mg/kg, intramuscularly - i.m.). The effect of anandamide (6nmol, intracerebroventricularly - i.c.v.) and/or the CB1 receptor antagonist SR141716A (30μg, i.c.v.) on haloperidol-induced vacuous chewing movements (VCMs) was assessed 28days after the start of the haloperidol treatment. Anandamide reversed haloperidol-induced VCMs; SR141716A (30μg, i.c.v.) did not alter haloperidol-induced VCM per se but prevented the effect of anandamide on VCM in rats. These results suggest that CB1 receptors may prevent haloperidol-induced VCMs in rats, implicating CB1 receptor-mediated cannabinoid signaling in orofacial dyskinesia.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2014; 54. DOI:10.1016/j.pnpbp.2014.04.006 · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antipsychotics may cause tardive dyskinesia in humans and orofacial dyskinesia in rodents. Although the dopaminergic system has been implicated in these movement disorders, which involve the basal ganglia, their underlying pathomechanisms remain unclear. CB1 cannabinoid receptors are highly expressed in the basal ganglia, and a potential role for endocannabinoids in the control of basal ganglia-related movement disorders has been proposed. Therefore, this study investigated whether CB1 receptors are involved in haloperidol-induced orofacial dyskinesia in rats. Adult male rats were treated for four weeks with haloperidol decanoate (38 mg/kg, intramuscularly – i.m.). The effect of anandamide (6 nmol, intracerebroventricularly - i.c.v.) and/or the CB1 receptor antagonist SR141716A (30 μg, i.c.v.) on haloperidol-induced vacuous chewing movements (VCMs) was assessed 28 days after the start of the haloperidol treatment. Anandamide reversed haloperidol-induced VCMs; SR141716A (30 μg, i.c.v.) did not alter haloperidol-induced VCM per se but prevented the effect of anandamide on VCM in rats. These results suggest that CB1 receptors may prevent haloperidol-induced VCMs in rats, implicating CB1 receptor-mediated cannabinoid signaling in orofacial dyskinesia.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2014; · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is biochemically characterized by the occurrence of extracellular deposits of amyloid beta peptide (Aβ) and intracellular deposits of the hyperphosphorylated tau protein, which are causally related to the pathological hallmarks senile plaques and neurofibrillary tangles. Monoamine oxidase B (MAO-B) activity, involved in the oxidation of biogenic monoamines, is particularly high around the senile plaques and increased in AD patients in middle to late clinical stages of the disease. Selegiline is a selective and irreversible MAO-B inhibitor and, although clinical trials already shown the beneficial effect of selegiline on cognition of AD patients, its mechanism of action remains to be elucidated. Therefore, we first investigated whether selegiline reverses the impairment of object recognition memory induced by Aβ25-35 in mice, an established model of AD. In addition, we investigated whether selegiline alters MAO-B and MAO-A activities in the hippocampus, perirhinal and remaining cerebral cortices of Aβ25-35-injected male mice. Acute (1 and 10 mg/kg, p.o., immediately post-training) and subchronic (10 mg/kg, p.o., seven days after Aβ25-35 injection and immediately post-training) administration of selegiline reversed the cognitive impairment induced by Aβ25-35 (3 nmol, i.c.v.). Acute administration of selegiline (1 mg/kg, p.o.) in combination with Aβ25-35 (3 nmol) decreased MAO-B activity in the perirhinal and remaining cerebral cortices. Acute administration of selegiline (10 mg/kg, p.o.) decreased MAO-B activity in hippocampus, perirhinal and remaining cerebral cortices, regardless of Aβ25-35 or Aβ35-25 treatment. MAO-A activity was not altered by selegiline or Aβ25-35. In summary, the current findings further support a role for cortical monoaminergic transmission in the cognitive deficits observed in AD.
Neurochemical Research 09/2013; 38(11). DOI:10.1007/s11064-013-1137-6 · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neuropathic pain is a debilitating condition that is often resistant to common analgesics, such as opioids, but is sensitive to some antidepressants, an effect that seems to be mediated by spinal cord 5-HT3 receptors. Because the analgesic potential of monoamine oxidase-A (MAO-A) inhibitors is understudied, we evaluated the potential antinociceptive effect of the reversible MAO-A inhibitors moclobemide and 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in a mouse neuropathic pain model induced by chronic constriction injury (CCI) of the sciatic nerve. Neuropathic mice showed a decreased mechanical paw withdrawal threshold (PWT) 7days after lesion compared with the baseline PWT, characterizing the development of hyperalgesia. Moclobemide (100-300μmol/kg, s.c.) and 2-DMPI (30-300μmol/kg, s.c.) treatments were able to reverse the CCI-induced hyperalgesia, with 50% inhibitory dose (ID50) values of 39 (18-84) and 11 (4-33) μmol/kg, and maximum inhibition (Imax) values of 88±14 and 98±15%, respectively, at the 300μmol/kg dose. In addition, we observed a significant increase in the MAO-A activity in the lumbar spinal cord of CCI-submitted mice compared with sham-operated animals. Furthermore, the antihyperalgesic effects of both 2-DMPI and moclobemide were largely reversed by intrathecal injection of the 5-HT3 receptor antagonist ondansetron (10μg/site). These results suggest a possible involvement of MAO-A in the mechanisms of neuropathic pain and a potential utility of the reversible inhibitors of MAO-A in the development of new therapeutic approaches to treat it.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 02/2013; 44. DOI:10.1016/j.pnpbp.2013.02.005 · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Administration of the compound triterpene 3β, 6β, 16β-trihidroxilup-20(29)-ene (TTHL) resulted in antinociceptive activity in several pain models in mice. Because pain and epilepsy have common mechanisms, and several anticonvulsants are clinically used to treat painful disorders, we investigated the anticonvulsant potential of TTHL. Behavioral and electrographic recordings revealed that pretreatment with TTHL (30 mg/kg; i.g.) increased the latencies to the first clonic seizure to the tonic-clonic and reduced the duration of the generalized seizures induced by the GABA(A) receptor antagonist PTZ (80 mg/Kg; i.p.). The TTHL pretreatment also protected against PTZ-induced deleterious effects, as characterized by protein carbonylation, lipid peroxidation, [(3)H] glutamate uptake and the inhibition of Na(+),K(+)-ATPase (subunits α(1)and α(2)/α(3)). Although TTHL did not exhibit DPPH, ABTS radical scavenging activity per se and does not alter the binding of [(3)H]flunitrazepam to the benzodiazepinic site of the GABA(A) receptor, this compound was effective in preventing behavioral and EEG seizures, as well as the inhibition of Na(+),K(+)-ATPase induced by ouabain. These results suggest that the protection against PTZ-induced seizures elicited by TTHL is due to Na(+),K(+)-ATPase activity maintenance. In fact, experiments in homogenates of the cerebral cortex revealed that PTZ (10 mM) reduced Na(+),K(+)-ATPase activity and that previous incubation with TTHL (10 μM) protected against this inhibition. Collectively, these data indicate that the protection exerted by TTHL in this model of convulsion is not related to antioxidant activity or GABAergic activity. However, these results demonstrated that the effective protection of Na(+),K(+)-ATPase elicited by this compound protects against the damage due to neuronal excitability and oxidation that is induced by PTZ.
[Show abstract][Hide abstract] ABSTRACT: Allosteric modulation of G-protein-coupled receptors represents a key goal of current pharmacology. In particular, endogenous allosteric modulators might represent important targets of interventions aimed at maximizing therapeutic efficacy and reducing side effects of drugs. Here we show that the anti-inflammatory lipid lipoxin A(4) is an endogenous allosteric enhancer of the CB(1) cannabinoid receptor. Lipoxin A(4) was detected in brain tissues, did not compete for the orthosteric binding site of the CB(1) receptor (vs. (3)H-SR141716A), and did not alter endocannabinoid metabolism (as opposed to URB597 and MAFP), but it enhanced affinity of anandamide at the CB1 receptor, thereby potentiating the effects of this endocannabinoid both in vitro and in vivo. In addition, lipoxin A(4) displayed a CB(1) receptor-dependent protective effect against β-amyloid (1-40)-induced spatial memory impairment in mice. The discovery of lipoxins as a class of endogenous allosteric modulators of CB(1) receptors may foster the therapeutic exploitation of the endocannabinoid system, in particular for the treatment of neurodegenerative disorders.
Proceedings of the National Academy of Sciences 11/2012; 109(51). DOI:10.1073/pnas.1202906109 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have recently demonstrated that rodents treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) suffered impairments in olfactory, cognitive, emotional and motor functions associated with time-dependent disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). Agmatine, an endogenous arginine metabolite, has been proposed as a novel neuromodulator that plays protective roles in several models of neuronal cellular damage. In the present study we demonstrated that repeated treatment with agmatine (30mg/kg, i.p.) during 5 consecutive days increased the survival rate (from 40% to 80%) of 15-month-old C57BL/6 female mice infused with a single intranasal (i.n.) administration of MPTP (1mg/nostril), improving the general neurological status of the surviving animals. Moreover, pretreatment with agmatine was found to attenuate short-term social memory and locomotor activity impairments observed at different periods after i.n. MPTP administration. These behavioral benefits of exogenous agmatine administration were accompanied by a protection against the MPTP-induced decrease of hippocampal glutamate uptake and loss of dopaminergic neurons in the substantia nigra pars compacta of aging mice, without altering brain monoamine oxidase B (MAO-B) activity. These results provide new insights in experimental models of PD, indicating that agmatine represents a potential therapeutic tool for the management of cognitive and motor symptoms of PD, together with its neuroprotective effects.
Behavioural brain research 08/2012; 235(2):263-72. DOI:10.1016/j.bbr.2012.08.017 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The transient receptor potential ankyrin 1 (TRPA1) is expressed in peripheral and spinal terminals of sensory neurons, jointly to the vanilloid receptor (TRPV1). A relevant peripheral role of TRPA1 receptor has been implicated in a variety of processes, including the detection of noxious cold, and diverse painful stimulus, but the functional role of TRPA1 receptor in nociceptive transmission at spinal cord in vivo is poorly known. Therefore, the aim of this study was to evaluate whether the glutamatergic system is involved in the transmission of nociceptive stimulus induced for a TRPA1 agonist in the rat spinal cord. We observed that cinnamaldehyde, a TRPA1 agonist, on spinal cord synaptosomes leads to an increase in [Ca(2+)](i) and a rapid release of glutamate, but was not able to change the specific [(3)H]-glutamate binding. In addition, spinally administered cinnamaldehyde produced heat hyperalgesia and mechanical allodynia in rats. This behavior was reduced by the co-injection (i.t.) of camphor (TRPA1 antagonist) or MK-801 (N-methyl-D-aspartate (NMDA) receptor antagonist) to cinnamaldehyde. Besides, the pretreatment with resiniferatoxin (RTX), a potent TRPV1 agonist, abolished the cinnamaldehyde-induced heat hyperalgesia. Here, we showed that intrathecal RTX results in a decrease in TRPA1 and TRPV1 immunoreactivity in dorsal root ganglion. Collectively, our results demonstrate the pertinent participation of spinal TRPA1 in the possible enhancement of glutamatergic transmission of nociceptive signals leading to increase of the hypersensitivity, here observed as heat hyperalgesia. Then the modulation of spinal TRPA1 might be a valuable target in painful conditions associated with central pain hypersensitivity.
[Show abstract][Hide abstract] ABSTRACT: In this study we assessed the involvement of monoamine oxidase B (MAO-B), a key enzyme implicated in monoamine metabolism, on postoperative (plantar incision) and neuropathic (partial sciatic nerve ligation) pain models in mice. Paw incision submitted mice showed a significant decrease in mechanical threshold compared with the sham-operated mice, characterizing the development of mechanical allodynia. The selective and irreversible MAO-B inhibitor selegiline, at a dose sufficient to selectively inhibit MAO-B activity (10 mg/kg), showed an anti-allodynic effect from 0.5 to 6 h after incision. Likewise, partial sciatic nerve ligation submitted mice also developed mechanical allodynia, which was reversed by selegiline (10 mg/kg) from 2 to 6 h after treatment. In addition, a significant increase on striatal MAO-B activity was observed in neuropathic mice compared with the sham-operated animals, which was reversed by selegiline treatment. Taken together, our results showed that MAO-B seems to exert a critical role in the development of postoperative and neuropathic pain.
European journal of pharmacology 07/2012; 690(1-3):107-14. DOI:10.1016/j.ejphar.2012.06.042 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Monoamine oxidase (MAO) inhibitors were the first antidepressant drugs to be prescribed and are still used today with great success, especially in patients resistant to other antidepressants. In this study, we evaluated the MAO inhibitory properties and the potential antidepressant action of 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in mice. We found that 2-DMPI inhibited both MAO isoforms (K(i) values were 1.53 (1.3-1.8) μM and 46.67 (31.8-68.4) μM for MAO-A and MAO-B, respectively) with 30-fold higher selectivity toward MAO-A. In relation to the nature of MAO-A inhibition, 2-DMPI showed to be a mixed and reversible inhibitor. The treatment with 2-DMPI (100-1000 μmol/kg, s.c.) caused a significant decrease in immobility time in the tail suspension test (TST) without affecting locomotor activity, motor coordination or anxiety-related activities. Conversely, moclobemide (1000 μmol/kg, s.c.) caused a significant increase in immobility time in the TST, which appeared to be mediated by a nonspecific effect on motor coordination function. 2-DMPI (300 μmol/kg, s.c.) decreased serotonin turnover in the cerebral cortex, hippocampus and striatum, whereas dopamine turnover was diminished only in the striatum, and norepinephrine turnover was not changed. The antidepressant-like effect of 2-DMPI was inhibited by the pretreatment of mice with methysergide (2 mg/kg, s.c., a non-selective serotonin receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) or haloperidol (0.05 mg/kg, i.p., a non-selective dopamine receptor antagonist). These results suggest that 2-DMPI is a prototype reversible and preferential MAO-A inhibitor with potential antidepressant activity, due to its modulatory effect on serotonergic and dopaminergic systems.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2012; 39(1):31-9. DOI:10.1016/j.pnpbp.2012.04.007 · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The compound 2-(2-benzofuranyl)-2-imidazoline (2-BFI) is a 2-imidazoline derivative that selectively inhibits the in vitro activity of monoamine oxidase-A and it is also an imidazoline I(2) agonist. However, the antidepressant potential of this compound and its mechanism of action have not been well defined. Therefore, in this study we investigated the antidepressant-like effect of 2-BFI in mice. 2-BFI (100 and 300μmol/kg, s.c.) significantly reduced the immobility time on the tail suspension test (TST) without changing locomotion in the open field test. The reduced the immobility time of 2-BFI (100μmol/kg, s.c.) was confirmed with the forced swimming test (FST). The antidepressant-like effect of 2-BFI (100μmol/kg, s.c.) in the TST was prevented by pretreatment with idazoxan (0.4μmol/kg, i.p., a I(2) site antagonist), methysergide (4μmol/kg, i.p., a non-selective serotonergic receptor antagonist) and haloperidol (0.1μmol/kg, i.p., a non-selective dopaminergic receptor antagonist). The anxiolytic effect of 2-BFI was also evaluated, using the elevated plus-maze test. 2-BFI (300μmol/kg, s.c.) was able to significantly increase the % of number of entries and the % of time spent in the open arms, indicating that it possesses an anxiolytic effect at high doses. In conclusion, these results suggest that the antidepressant-like effect of 2-BFI might involve serotonergic, dopaminergic and imidazoline systems, and then the imidazoline site could represent a new pharmacological target for the treatment of depression.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 11/2011; 37(1):15-21. DOI:10.1016/j.pnpbp.2011.11.005 · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have recently demonstrated that rodents treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) suffered
impairments in olfactory, cognitive and motor functions associated with time-dependent disruption of dopaminergic neurotransmission
in different brain structures conceivably analogous to those observed during different stages of Parkinson’s disease (PD).
On the other hand, the proanthocyanidin-rich fraction (PRF) obtained from the bark of Croton celtidifolius Baill (Euphorbiaceae), a tree frequently found in the Atlantic forest in south Brazil, has been described to have several
neurobiological activities including antioxidant and anti-inflammatory properties, which may be of interest in the treatment
of PD. The present data indicated that the pretreatment with PRF (10mg/kg, i.p.) during five consecutive days was able to
prevent mitochondrial complex-I inhibition in the striatum and olfactory bulb, as well as a decrease of the enzyme tyrosine
hydroxylase expression in the olfactory bulb and substantia nigra of rats infused with a single intranasal administration
of MPTP (1mg/nostril). Moreover, pretreatment with PRF was found to attenuate the short-term social memory deficits, depressive-like
behavior and reduction of locomotor activity observed at different periods after intranasal MPTP administration in rats. Altogether,
the present findings provide strong evidence that PRF from C. celtidifolius may represent a promising therapeutic tool in PD, thus being able to prevent both motor and non-motor early symptoms of PD,
together with its neuroprotective potential.
[Show abstract][Hide abstract] ABSTRACT: The transient potential vanilloid 1 receptor (TRPV1) is a calcium-permeable channel responsible for the transduction and modulation of acute and chronic pain signaling. As such, this receptor is a potential target for the treatment of a number of pain disorders. However, AMG517, a TRPV1 antagonist, presents several clinical limitations that include the induction of severe hyperthermia. The aim of this study was to investigate the possible interaction of the flavonoid eriodictyol with the TRPV1 receptor and to determine its putative antinociceptive and hyperthermic effects. Eriodictyol was able to displace [(3)H]-resiniferatoxin binding (IC(50)=47; 21-119nM) and to inhibit calcium influx mediated by capsaicin (IC(50)=44; 16-125nM), suggesting that eriodictyol acts as a TRPV1 antagonist. Moreover, eriodictyol induced antinociception in the intraplantar capsaicin test, with maximal inhibition of 49±10 and 64±4% for oral (ID(50)=2.3; 1.1-5.7mg/kg) and intrathecal (ID(50)=2.2; 1.7-2.9nmol/site) administration, respectively. Eriodictyol did not induce any change in body temperature or locomotor activity. Orally administered eriodictyol (4.5mg/kg) prevented the nociception induced by intrathecal injections of capsaicin, as well as the non-protein thiol loss and 3-nitrotyrosine (3-NT) formation induced by capsaicin in spinal cord. Eriodictyol also reduced the thermal hyperalgesia and mechanical allodynia elicited by complete Freund's adjuvant (CFA) paw injection. In conclusion, eriodictyol acts as an antagonist of the TRPV1 receptor and as an antioxidant; it induces antinociception without some of the side effects and limitations such as hyperthermia that are expected for TRPV1 antagonists.
[Show abstract][Hide abstract] ABSTRACT: Methamidophos (Meth) is a toxic organophosphorus compound (OP) that inhibits acetylcholinesterase enzyme (AChE) and induces neurotoxicity. As the mechanism of its neurotoxic effects is not well understood, the aim of the present study was to evaluate the effects of Meth on glutamate and gamma aminobutyric acid (GABA) uptake and correlate with cell viability and AChE and Na(+)/K(+)-ATPase enzyme activities in striatum and hippocampus slices exposed to low concentrations (0.05 to 1.0 μM) of Meth.
Hippocampal and striatal slices of rat brain were exposed to Meth for 5 min ([(3)H]Glutamate uptake) or 15 min ([(3)H]GABA uptake) for assays. The enzyme activities and cell viability were also accessed at both times in hippocampal and striatal slices and homogenates.
At concentrations that did not inhibit AChE, Meth caused changes in glutamate uptake in striatal (0.05 and 1.0 μM Meth) and hippocampal (1.0 μM Meth) slices. GABA uptake was increased by the pesticide in striatum at 0.5 and 1.0 μM and in hippocampus at 0.05 μM. After 3.5h of Meth exposure, striatal and hippocampal cells showed no changes in viability as well as no inhibition of Na(+)/K(+)-ATPase were observed after 5 or 15 min exposure to Meth in the same brain structures.
Results suggest that Meth, even without changing the AChE activity can modify somehow the neurotransmitters uptake. However, further studies are necessary to clarify if this modulation in glutamate or GABA uptake may be responsible to cause some disturbance in behavior or in other neurochemical parameters following low Meth exposure in vivo.
Life sciences 11/2010; 88(1-2):89-95. DOI:10.1016/j.lfs.2010.10.031 · 2.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Here we evaluate the influence of a new exercise protocol on movement disorders induced by neuroleptic drugs. In this animal model, involuntary movements are closely related to neuronal degeneration and oxidative stress (OS) that can be caused by pre-synaptic D2 receptor blockade increasing dopamine (DA) metabolism. The increase in vacuous chewing movements (VCM) and the reduced locomotor activity induced by haloperidol treatment (12 mg/kg-im, once a week for 4 weeks) was prevented by exercise, 5 times per week, which was initiated four weeks before the first haloperidol administration. Exercise training also prevented the increase of haloperidol-induced lipid peroxidation in the cortex and subcortical region and recovered the catalase activity in the subcortical region. There was a negative correlation between catalase activity in the subcortical region and the VCM frequency (r = 0.50, p < 0.05), as well as a positive correlation between VCM frequency and lipid peroxidation in the cortex (r = 0.64, p < 0.05) and subcortical region (r = 0.71, p < 0.0001). Both haloperidol and exercise increased DA uptake in the striatum, while the co-treatment (exercise plus haloperidol) reduced it. The striatal DA uptake correlated negatively with catalase activity (r = 0.51, p < 0.05), indicating a relationship between oxidative damage and the function of the transporter in the striatum. Our findings show that physical exercise can modulate dopamine uptake, especially when it is altered, and reveal the benefit of this new exercise protocol in the prevention of movement disorders related to oxidative damage.
[Show abstract][Hide abstract] ABSTRACT: This study was designed to determine whether the treatment with haloperidol (HP), valerian or both in association impairs the liver or kidney functions. Valerian alone did not affect oxidative stress parameters in the liver or kidney of rats. HP alone only increased glutathione (GSH) depletion in liver, but not in kidney. However, when HP was associated with valerian, an increase in lipid peroxidation levels and dichlorofluorescein (DCFH) reactive species production was observed in the hepatic tissue. Superoxide dismutase (SOD) and Catalase (CAT) activities were not affected by the HP plus valerian treatment in the liver and kidney of rats. HP and valerian when administered independently did not affect the activity of hepatic and renal delta-aminolevulinate dehydratase (delta-ALA-D), however, these drugs administered concomitantly provoked an inhibition of hepatic delta-ALA-D activity. The delta-ALA-D reactivation index was higher in rats treated with HP plus valerian than other treated groups. These results strengthen the view that delta-ALA-D can be considered a marker for oxidative stress. Serum aspartate aminotransferase (AST) activity was not altered by any treatment. However, serum alanine aminotransferase (ALT) activity was higher in the HP group and HP plus valerian group. Our findings suggest adverse interactions between haloperidol and valerian.
Food and Chemical Toxicology 08/2008; 46(7):2369-75. DOI:10.1016/j.fct.2008.03.019 · 2.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic treatment with classical neuroleptics in humans can produce a serious side effect, known as tardive dyskinesia (TD). Here, we examined the effects of V. officinalis, a medicinal herb widely used as calming and sleep-promoting, in an animal model of orofacial dyskinesia (OD) induced by long-term treatment with haloperidol. Adult male rats were treated during 12 weeks with haloperidol decanoate (38 mg/kg, i.m., each 28 days) and with V. officinalis (in the drinking water). Vacuous chewing movements (VCMs), locomotor activity and plus maze performance were evaluated. Haloperidol treatment produced VCM in 40% of the treated rats and the concomitant treatment with V. officinalis did not alter either prevalence or intensity of VCMs. The treatment with V. officinalis increased the percentage of the time spent on open arm and the number of entries into open arm in the plus maze test. Furthermore, the treatment with haloperidol and/or V. officinalis decreased the locomotor activity in the open field test. We did not find any difference among the groups when oxidative stress parameters were evaluated. Haloperidol treatment significantly decreased [(3)H]-dopamine uptake in striatal slices and V. officinalis was not able to prevent this effect. Taken together, our data suggest a mechanism involving the reduction of dopamine transport in the maintenance of chronic VCMs in rats. Furthermore, chronic treatment with V. officinalis seems not produce any oxidative damage to central nervous system (CNS), but it also seems to be devoid of action to prevent VCM, at least in the dose used in this study.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 11/2007; 31(7):1478-86. DOI:10.1016/j.pnpbp.2007.06.028 · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic treatment with neuroleptics causes, as a side effect, tardive dyskinesia in humans; however, the mechanisms involved in its pathophysiology remain unclear.
The purpose of this study was to examine the effects of diphenyl diselenide, an organoselenium compound with antioxidant properties, in an animal model of vacuous chewing movements (VCMs) induced by long-term treatment with fluphenazine.
Adult male rats were treated during 24 weeks with fluphenazine (25 mg/kg, intramuscularly [i.m.], once every 21 days) and diphenyl diselenide (1 mg/kg, subcutaneously, three times a week). VCMs and body weight gain were quantified every 3 weeks. The fluphenazine treatment produced VCMs in the majority of the treated rats (87% after 24 weeks). Concomitant treatment with diphenyl diselenide decreased the prevalence of VCMs to 50%. Additionally, we separated the rats that developed or did not develop VCMs. We did not find any statistical differences among the groups when oxidative stress parameters were evaluated. Chronic fluphenazine treatment significantly decreased [(3)H]-dopamine uptake. Concomitant treatment with diphenyl diselenide was not able to prevent this decrease in those rats that developed VCMs.
Our data suggest that the reduction in dopamine transport can be a possible mechanism related to the maintenance of VCMs in rats. Moreover, diphenyl diselenide seems to be a promising pharmacological agent in the reduction in the prevalence of VCMs in rats.