Central Nervous System Agents in Medicinal Chemistry(Formerly Current Medicinal Chemistry - Central Nervous System Agents) (Cent Nerv Syst Agents Med Chem)

Publisher: Bentham Science Publishers

Journal description

Central Nervous System Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of new central nervous system agents. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics in central nervous system medicinal chemistry. Central Nervous System Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in central nervous system drug discovery. Formerly Current Medicinal Chemistry - Central Nervous System Agents (1568-0150).

RG Journal Impact: 0.77 *

*This value is calculated using ResearchGate data and is based on average citation counts from work published in this journal. The data used in the calculation may not be exhaustive.

RG Journal impact history

2019Available summer 2020
20150.77
20142.39
20132.19
20122.32
20112.91
20101.41

RG Journal impact over time

RG Journal impact
RG Journal impact over timeGraph showing a linear path with a yearly representation of impact points of the journal

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Websitehttp://www.bentham.org/cmccnsa/
Website descriptionCentral Nervous System Agents in Medicinal Chemistry website
ISSN1875-6166
OCLC229181566
Material typePeriodical
Document typeJournal / Magazine / Newspaper

Publications in this journal

O-1602 is a cannabidiol analogue that does not bind with high affinity to either the cannabinoid CB1 receptor or CB2 receptor. However, there is evidence that O-1602 has significant effects in the central nervous system as well as other parts of the body. Depending upon the model, O-1602 has anti-inflammatory or pronociceptive effects, mediated through a number of distinct receptors. This article reviews the evidence for functional effects of O-1602, particularly in the CNS, and describes its known targets as they relate to these effects. These include the abnormal cannabidiol (Abn- CBD) receptor and GPR55. The GPR18 receptor has been identified with the Abn-CBD receptor, and therefore the evidence that O-1602 also acts at GPR18 is also reviewed. Finally, the evidence that these receptor targets are expressed in the CNS and the phenotypes of cells expressing these targets is discussed, concluding with a discussion of the prospects for O-1602 as a therapeutic agent in the CNS.
Previously we have reported 5-substituted phenyl-3-(thiophen-2-yl)-4, 5-dihydro-1h-pyrazole-1-carboxamides as a novel class of antidepressants. The aim of the current study is to proposing the reason for such biological activities of the molecules by using molecular docking studies using AutoDock4.2. Using molecular docking studies, we propose that most of the antidepressant molecules showed good binding affinity towards MAO-A than MAO-B which is an effective target for the treatment of depression. The R and S form of thiophene based pyrazolines-carboxamides showed a binding energy and inhibition constant between 7.93 to -8.76 and 1.54 to 0.38 µM toward MAO-A and -6.39 to -8.51 and 20.84 to 0.57 µM toward MAO-B respectively.
Herein the evolution in the development of new sigma (sigma) receptor ligands since the middle '90s by our research group is reported. In the effort to contribute to the identification of the structural features for high-affinity ligands selective versus serotonin, dopamine and other CNS-related receptors, two general classes of (naphthalene)alkylamine compounds were prepared and explored, with the aim of addressing the affinities toward the two recognized sigma receptor subtypes. The common template of these compounds was mainly an unsubstituted or methoxy-substituted naphthalene or tetralin nucleus, linked by an alkyl spacer to a substituted piperazine or piperidine ring. The design of new ligands was thought keeping in mind their possible application as PET diagnostic tools and fluorescence tools. High-affinity sigma(2) receptor ligands were found among N-cyclohexylpiperazine derivatives, such as 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (3) (PB 28), when they were assayed in radioligand binding with [(3)H]-DTG in rat liver. Unfortunately, these ligands were all devoid of a significant selectivity relative to sigma(1) receptor whose binding was assayed with (+)-[(3)H]-pentazocine in guinea pig brain. Nevertheless, compound 3 had previously shown to be 40-fold selective with a slightly different binding method in animals' tissues. Moreover, it demonstrated 46-fold and 59-fold sigma(2) versus sigma(1) receptor binding selectivity in MCF7 and MCF7 ADR tumor cell lines respectively. In the class of piperazines, also high-affinity sigma(1) receptor ligands were found, possibly due to the presence of a double N-atom and an additional reverse mode of binding. Piperidine derivatives were investigated as high-affinity and selective sigma(1) receptor ligands leading to some 3,3-dimethylpiperidines such as 3,3-dimethyl-1-[3-(6-methoxynaphthalen-1-yl)propyl]piperidine (69) which resulted to be highly selective relative to the sigma(2) receptor. For the best ligands, functional assays were conducted in order to investigate agonist/antagonist activity. The effect of chirality in the intermediate methyl-alkyl chain was explored for a class of 4-methylpiperidines linked to some (4-chlorophenoxy)alkyl moieties, and compound (-)-(S)-92 emerged as the most selective sigma(1) relative to sigma(2) receptor ligand.
Monoamine oxidase B inhibitors are of particular importance in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Herein described is pharmacophore generation and atom-based 3D-QSAR analysis of previously reported furan based MAO-B inhibitors in order to get insight into their structural requirements responsible for high affinity. The best pharmacophore model generated with the five-point hypotheses of ADHRR: hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic (H) and two aromatic rings (R1 & R2). On the basis of generated model, a statistically valid 3D-QSAR with good predictability was developed. Molecular docking of lead compound showed binding energy of -8.66 kcl/mol with a predicted inhibition constant of 0.448 µM towards MAO-B.
Genetic factors that increase susceptibility to oxidative stress, endothelial disfunction and, possibly, stroke include angiotensin-converting enzyme gene deletion polymorphism (ACE-DD) and the methylentetrahydropholate reductase (MTHFR) C677-TT polymorphism. The relationship of ACE-DD genotype to ischemic stroke and cardiovascular disease is controversial, but it has been independently linked to lacunar infarction, in the absence of carotid atheroma. Lea et al. (2005) reported that the ACE DD genotype acts in combination with the MTHFR T/T genotype to increase migraine susceptibility, with the greatest effect in those with aura. The "TT" polymorphism is also associated with an increased risk of migraine with aura, independent of other cardiovascular risk factors. The aim of our study was to evaluate the incidence of ACE and MTHFR genes polymorphisms in a consecutive series of migrainous patients and of patients affected by myocardial infarction. We studied a series of 103 migrainous patients (1), whose age was between 13 and 75 years (81 suffering from migraine without aura, MwA, 9 from migraine with aura, MWA, 13 from mixed forms MwA-MWA, according to ICHD-II 2004 criteria) and of 336 patients (2) suffering from ischaemic cardiopathy (myocardial infarction, MI). The analysis, based on Polymerase Chain Reaction (PCR) and on reverse-hybridization, showed as follows: MTHFR (C677T): 60 patients (58%) (1) and 186 (56%) (2) were heterozygous; 9 patients (9%) (1) and 54 (16%) (2) were mutated. The result of 1 patient (2) was unknown. MTHFR (A1298C): 54 patients (52%) (1) and 146 (44%) (2) were heterozygous, 7 patients (7%) (1) and 33 (10%) (2) were mutated. The result of 1 patient (2) was unknown. ACE (evaluated on 101 patients (1) and 245 (2)): 45 patients (43%) (1) and 133 (54%) (2) had an ID genotype; 42 (41%) (1) and 87 (36%) (2) had a DD genotype. The results of our study confirm the high incidence in the genetic polymorphisms ACE and MTHFR in migraineuse. These data are confirmed in the sample of patients affected by myocardial infarction. This gives evidence of a strong relationship between migraine and major vascular diseases and let us hypothesize an important role of ACE and MTHFR system in the pathogenetic model of migraine for its capability to interfere with the endothelial regulation tone. Once an effective role in the genesis of migraine and in the increased risk of migrainous patients to evolve into an ischemic pathology has been obviously assigned to this genetic mutation, future researches must aim through wider and more controlled casistics also to clarify the role that drugs acting on these systems may have on the resolution of these diseases.
In view of the large libraries of acetylcholinesterase inhibitors (AChEIs) that are now being handled in organic synthesis, the identification of drug biological activity is advisable prior to synthesis and this can be achieved by employing predictive biological property methods. In this sense, Quantitative Structure-Activity Relationships (QSAR) or docking approaches have emerged as promising tools. The intention of this review is to summarize the present knowledge concerning computational predictions of AChEIs and AChE.
Migraine is a primary headache disorder with an unknown pathophysiology. The growing evidence in recent years indicates migraine being a brain disorder, a sensory dysmodulation, and a system failure of normal sensory processing of the brainstem that involves the vascular tone and pain. At the moment, triptan family and NSAIDs are the first choice drugs for the treatment of acute migraine. There are several prophylactic drugs including the antiepileptic drugs (AEDs), betablockers, and Ca2+ channel blockers that are used for the treatment of migraine. Although many drugs including the triptans, NSAIDs, and others target the peripheral sites of activation, several novel drugs are being developed to target neural sites of action in the central nervous system (CNS). The first trigeminal synapses in the brain stem as well as the ascending and descending pathways and higher brain centers are involved in the transmission of pain and therefore be the main targets of several drugs some of which are in clinical trials. Central sensitization may also aggravate the headache and some drugs tend to alleviate pain by targeting neurotransmitters, receptors, or signalling molecules involved in this phenomenon. This article discusses the CNS acting novel drugs and those that are currently in use for the treatment of migraine.
Epidemiological studies have shown positive preventive action of flavonoids on cardiovascular and neurodegenerative events. Among the six groups in which flavonoids are classified, the flavones and flavonols, based on the backbone of 2-phenylchromen-4-one (2-phenyl-1-benzopyran-4-one) are the most commonly encountered within the families and genera of the higher plants. Numerous studies support a neuroprotective activity of flavones such as luteolin and flavonols such as kaempherol and quercetin in experimental focal ischemia and models of neurodegeneration. Antioxidations, modulation of signaling cascades and gene expressions as well as anti-inflammation appear as the main protective mechanisms and mitochondria are a likely main target mediating the preventive actions against oxidative stress. Flavones and flavonols re-establish the redox regulation of proteins, transcription factors and signaling cascades that are otherwise inhibited by elevated oxidative stress. The final survival or death of the neuron depends on flavone and flavonol concentrations, time of exposure and, mainly, metabolic and oxidative neuronal circumstances. Neuroprotection appears to be linked to specific structural motifs, beyond those involved in antioxidation. By themselves or as templates for synthetic compounds, flavone and flavonol molecules show potential as multi-targeted therapeutic tools for protecting the brain. Nonetheless, more research needs to be done on the correlation of potential beneficial effects of flavones and flavonols and their mechanisms of action.
Xanthine Oxidase (XO; EC. 1.1.3.22) and Dihydropyrimidine Dehydrogenase (DPD; EC. 1.3.1.2) are two enzymes responsible for the last steps of purines and pyrimidines catabolism, hydroxylation of a wide variety of pyrimidine, pterin, and aldehyde substrates. Elion showed that purine isomers can be converted to various nucleotides, which influence pyrimidine metabolism (Elion, 1978). Current study is devoted to the delineation of the correlation between survival of the human brain derived cells in the culture and activities of XO along with DPD. Cultivation of (E90) brain cells was performed by the modified method of Mattson (1990). XO activity was measured by the formation of the uric acid in the tissue. DPD activity was evaluated by the reduction of NADPH and decrease of the absorbance at 320 nm. Cell death was detected by the utility of Trypan Blue dye. During our investigations we have noticed reversed correlation between activities of XO and DPD over 12 days in the normal conditions as well as in the presence of XO and DPD inhibitors: allopurinol and dipyridamol. During the treatment periods over 12 days, as well as from days 7-12th with the inhibitors, we have noticed cells protection, whereas treatment from days 1-7th elevated percentile of the death cells in the culture. Low dosage of allopurinol treatment over 12 days also stimulated cells growth and elevated number of the cells in the culture. We have concluded that timely inhibition of XO as well as DPD activities might initiate cells growth and preserve them from death.
Oxidative stress is a deleterious condition leading to cellular death. It plays a key role in the development and pathology of neurodegenerative diseases, like Alzheimer's disease (AD). AD is the most common form of dementia among elderly. Genetic mutations and genetic, acquired and environmental risk factors, particularly neuroinflammation and oxidative stress, are the main causes of AD. Neurogenesis occurs in the adult brain of mammals, particularly in the hippocampus, and is enhanced in the brain of patients with AD. Enhanced neurogenesis in AD may represent an attempt by the central nervous system to compensate for the neuronal loss and repair itself. Reactive oxygen species (ROS) promote cell death and the nondisjunction of chromosomes, leading to aneuploidy. The activity of ROS on newly generated neuronal cells in the adult brain may contribute to the pathogenesis of AD. Antioxidant may be used to reduce the deleterious activity of ROS, particularly on newly generated neuronal cells of the adult brain, potentially delaying the development of AD and promoting the regenerative capacity of the adult brain.
Multiple sclerosis (MS) is a disorder of the central nervous system (CNS). It is characterized by episodic and progressive neurological dysfunction resulting from inflammatory and autoimmune reactions, myelin loss, conduction block, oligodendrocyte pathology, gliosis, and axonal loss in CNS. Recent years have witnessed advances in better understanding the immune pathogenesis of MS, prompted by animal models, human pathological observations and MRI studies. There have been significant changes in the therapeutic regimens in MS, with an emphasis on preventative treatment of an ongoing disease process. Agents in use and in the research pipeline have mechanisms that act on various anti-inflammatory and immunomodulatory properties, including blocking leukocyte migration into CNS and targeting chemoattraction. In addition, recent studies on the neurodegenerative components of MS have directed therapeutic trials to neuroprotection and neurorestoration. In this paper, we summarize the current understanding of the mechanisms of approved pharmacological agents and review the putative mechanisms and status of some important agents in clinical phase two or three trials in MS.
The therapies of mood and anxiety disorders are not solved, because current antidepressants have delayed onset of therapeutic action and a significant number of patients are non-responsive. Research on the field was leaning towards neuropeptides as therapeutic targets. Vasopressin (VP) is a hot candidate, as beyond its peripheral actions VP is implicated in interneuronal communication and modulates the hypothalamo-pituitary-adrenal (HPA), the key stress axis, as well as behavioural functions. Affective disorders are stress related disorders and the most frequently occurring abnormality in depressed subjects is hyperactivity of the HPA. VP with nucleus paraventricularis hypothalami origin is a direct adrenocorticotrophin secretagogue through its V1b receptor. VP seems to have special importance under prolonged stress conditions, which are known to be strong predictive factor of depressive disorder and can induce depressive-like symptoms. Preclinical and clinical data summarized in this review underline the importance of VP in the development of anxiety- and depressive-like symptoms. Orally active nonpeptiderg V1b antagonists were developed and seemed to have effective anxiolytic and antidepressant profile in preclinical studies, which was not fully confirmed by clinical observations. It seems that V1a receptors on special brain areas could have same importance. Taken together current knowledge strongly implies an importance of vasopressinergic regulation in affective disorders and consider VP as endogenous anxiogenic/depressogenic substance. However, wide range of sideeffects could develop as a result of an intervention on the VP system; therefore there is a need for area-specific.
It was postulated that N(6)-allyl bicyclic derivatives 1 bind with N-8 at the proton donor site of the sigma(1) receptor and that a substituent in 2-position of the bicyclic framework 1 results in unfavorable steric interactions with the sigma(1) receptor protein. In order to support this hypothesis both enantiomers of 6-allyl-8-(4-methoxybenzyl)-6,8-diazabi-cyclo[3.2.2]non-2-ene (2/ent-2) and 6-benzyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane 3/ent-3 were synthesized stereoselectively. The (S,S)-configured enantiomers 2 and 3 are the eutomers with eudismic ratios of 31 and 4.8, respectively. Therefore, these enantiomers are used in the sigma(1) pharmacophore model. The N(6)-allyl derivative 2 with a double bond in the three carbon bridge adopts the orientation 2c with N-8 interacting with the sigma(1) receptor proton donor site (Fig. 2) resulting in slightly reduced steric interactions of the small double bond in 2/3-position. The almost C(2)-symmetric benzyl derivative 3 can adopt both orientations 2c and 2d at the sigma (1) receptor (N-8 or N-6 interacts with the sigma (1) receptor proton donor site) resulting in subnanomolar sigma(1) receptor affinity (K(i) = 0.91 nM).
The disease activity of multiple sclerosis (MS) is known to be ameliorated during pregnancy, and pregnancy is also found to be protective in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Estrogen levels increase during pregnancy and basic researches have shown that estrogens have immunomodulatory effects on immune cells. The importance of estrogen in pathogenic autoimmune diseases has also been demonstrated in EAE by altering hormone levels. Mice treated with estrogen experienced significantly decreased EAE severity and delayed onset of disease as a result of neuroprotective and anti-inflammatory effects. Brain atrophy has been detected at the early stages of MS by using MRI; thus, as a neuroprotective agent, estrogen might be effective against brain atrophy. Estrogen's effects are primarily mediated by the nuclear estrogen receptor (ER), and recent studies have shown the presence of nuclear ERs on the cells involved in the immune response. There have been some reports on genetic polymorphisms of ERs in MS. In this review paper, we discuss increasing evidence that points to a link between estrogen and MS. We also analyze the therapeutic potential of estrogens in MS and review current genetic studies on ER.
Tuberculous meningitis is caused by Mycobacterium tuberculosis, which is the bacteria that causes tuberculosis. This bacteria spreads to the brain from another site within the body. If untreated, tuberculous meningitis can be life-threatening. Substantial brain damage can result from infection which results in mental impairment, motor paralysis, seizures, and abnormal behavior. This study presents the analysis of the effectiveness of 13 novel tuberculostatic agents, along with isoniazid (a first-line drug utilized for treatment of Mycobacterium tuberculosis). All 13 agents retain a diverse character of molecular structure effectuating a range of molecular properties such as in polar surface area, Log P, and formula weight. Properties such as polar surface area, formula weight, and Log P were determined for these agents as well as values of BB (Cbrain/Cblood), and Log BB. Values of BB varied from 0.0681 to 1.16. Only three of the novel drug structures showed one violation of the Rule of 5, while the remaining showed zero violations (an outcome favoring bioavailability). Values of polar surface area ranged from 55.121 Angstroms(2) to 110.24 Angstroms(2), and Log P from -3.52 to 4.965. This group of novel tuberculostatic agents reveals examples of three homologous series of tuberculostatic drugs which purposes the likelihood of as many as 20 effective tuberculostatic drugs. Determination of MIC60 disclosed eight novel structures matching the effectiveness of isoniazid, while two showed superior ability to deter Mycobacterium tuberculosis proliferation. These novel drug designs are shown to have substantial potential for the beneficial treatment of patients having infections of Mycobacterium tuberculosis within the central nervous system.
Stroke is the third leading cause of mortality and disability in the United States. Ischemic stroke constitutes 85% of all stroke cases. However, no effective treatment has been found to prevent damage to the brain in such cases except tissue plasminogen activator with narrow therapeutic window, and there is an unmet need to develop therapeutics for neuroprotection from ischemic stroke. Studies have shown that mechanisms including apoptosis, necrosis, inflammation, immune modulation, and oxidative stress and mediators such as excitatory amino acids, nitric oxide, inflammatory mediators, neurotransmitters, reactive oxygen species, and withdrawal of trophic factors may lead to the development of the ischemic cascade. Hence, it is essential to develop neuroprotective agents targeting either the mechanisms or the mediators leading to development of ischemic stroke. This review focuses on central nervous system agents targeting these biochemical pathways and mediators of ischemic stroke, mainly those that counteract apoptosis, inflammation, and oxidation, and well as glutamate inhibitors which have been shown to provide neuroprotection in experimental animals. All these agents have been shown to improve neurological outcome after ischemic insult in experimental animals in vivo, organotypic brain slice/acute slice ex vivo, and cell cultures in vitro and may therefore aid in preventing long-term morbidity and mortality associated with ischemic stroke.
Schizophrenia (SZ) that is resistant to treatment with dopamine (DA) D2 antagonists may involve changes other than those in the dopaminergic system. Recently, histamine (HA), which regulates arousal and cognitive functions, has been suggested to act as a neurotransmitter in the central nervous system. Four HA receptors-H1, H2, H3, and H4-have been identified. Our recent basic and clinical studies revealed that brain HA improved the symptoms of SZ. The H3 receptor is primarily localized in the central nervous system, and it acts not only as a presynaptic autoreceptor that modulates the HA release but also as a presynaptic heteroreceptor that regulates the release of other neurotransmitters such as monoamines and amino acids. H3-receptor inverse agonists have been considered to improve cognitive functions. Many atypical antipsychotics are H3-receptor antagonists. Imidazole-containing H3-receptor inverse agonists inhibit not only cytochrome P450 but also hERG potassium channels (encoded by the human ether-a-go-go-related gene). Several imidazole H3-receptor inverse agonists also have high affinity for H4 receptors, which are expressed at high levels in mast cells and leukocytes. Clozapine is an H4-receptor agonist; this agonist activity may be related to the serious side effect of agranulocytosis caused by clozapine. Therefore, selective non-imidazole H3-receptor inverse agonists can be considered as novel antipsychotics that may improve refractory SZ.
Methods for addressing sigma receptor affinity and activity have been explored and although several protocols have been employed, only few procedures resulted reliable. Sigma-1 receptor affinity protocol using guinea-pig brain and (+)-[(3)H]-pentazocine and sigma-2 receptor affinity protocol employing rat liver and [(3)H]-DTG are usually reported by authors as standard procedures. By contrast, the intrinsic activity evaluation of sigma ligands has been performed in several manners: tumor cell lines, isolated organ bath, in vivo animal model. The last is not considered in the present paper because this method studied the physiological role of sigma receptors. The studies carried out in tumor cell lines involved the role of sigma receptors in tumors progression while, although isolated organ bath experiment employed physiological samples, the pharmacokinetic properties of ligands, a strictly requirement for the in vivo assays, did not affect the pharmacodynamic properties of tested compounds. The advances in the above mentioned assays have been reported.
Increasing evidence of pro-inflammatory mediator expression in major depressions indicate that inflammatory changes may play a role. If this is true, the efficacy of antidepressants may be partially attributable to suppression of inflammation. Various types of antidepressants can suppress serum and plasma levels of pro-inflammatory mediators in patients with major depression. Therefore they can inhibit the production of pro-inflammatory mediators by immune cells. These include glial cells, which are the main sources and targets of cytokines in the brain. This review summarizes the evidence showing that antidepressants have an anti-inflammatory potential. The putative mechanisms are also discussed. Because of the anti-inflammatory effects of antidepressants, they might also act as preventives for neurodegenerative dementias including Alzheimer's disease, where the pathogenesis involves chronic inflammation associated with activated microglia.
A large number of therapeutic roles have been proposed for sigma(1) receptors but the involvement of sigma(1) receptor in non-acute pain had not been well explored up to now. sigma(1) receptor knock-out mice became available offering us the possibility to study the role of sigma(1) receptor in nociception, particularly in models where central sensitization processes play a significant role. Given the attractive therapeutic potential, we have developed a chemical program aimed at the discovery of novel and selective sigma(1) ligands. Herein we discuss the rational basis of this approach and report preliminary pharmacological results of several chemical series and aspects of their structure-activity relationship on sigma(1) receptor. Functional data in pain models are presented mainly on one series that provide evidence to consider selective sigma(1) receptor antagonists an innovative and alternative approach for treating neuropathic pain.
A series of thiosemicarbazones of halogen substituted benzaldehydes, benzophenone and acetophenone were synthesized using an appropriate synthetic route and characterized by thin layer chromatography and spectral analysis. The anticonvulsant activity of synthesized compounds was established in three seizures models which includes maximal electroshock (MES), subcutaneous pentylene tetrazole (scPTZ) induced seizures and minimal neurotoxicity test. Five compounds out of 21 exhibited protection in MES test while only one compound showed protection in scPTZ screen. Two compounds were found to be active in minimal clonic seizure (6Hz) model. Compound PS6 i.e. 2-(3-bromobenzylidene)-N-(4-chlorophenyl) hydrazinecarbothioamide emerged as the most active compound with MES ED50 of more than 50mg/kg and pI greater than 12, which is found to be better than the prototype drug, Phenytoin. The compound has shown neuroprotection in kainic acid model with IC50 value of 40.97 µM. It has also shown mild activation effect on CYP 269 and CYP 2C9 enzymes, indicating the usefulness of thiosemicarbazones as anticonvulsants.
Convolvulus pluricaulis Choisy is a perennial wild herb commonly found on sandy & rocky areas under xerophytic conditions in northern India. It is a reputed drug of ayurveda and reported to posses antioxidant, brain tonic, nervine tonic, laxative and has been used in anxiety, neurosis, epilepsy, insomnia, burning sensation, oedema and urinary disorders. In the present study, methanolic extract of whole plant of Convolvulus pluricaulis Choisy was evaluated for antioxidant activity by using 1, 1-diphenyl-2-picryl- hydrazyl (DPPH) free radical scavenging model and anticonvulsant activity by using maximal electroshock seizure model. In antioxidant activity, ascorbic acid was used as standard agent while results of anticonvulsant studies were compared with phenytoin. Results of antioxidant activity have demonstrated significant free radical scavenging effect for methanolic extract of Convolvulus pluricaulis Choisy. IC50 value of methanolic extract was observed as 41.00μg/ml as compared to 2.03μg/ml of ascorbic acid. Methanolic extract of C. pluricaulis was evaluated for anticonvulsant activity at 250, 500 and 1000mg/kg. Experimental results have shown that at the dose of 500 and 1000mg/kg, C. pluricaulis didn't abolish the hind limb extension, but reduced the mean recovery time from convulsion.
Dysfunction of serotoninergic neurotransmission is known to be involved in the pathophysiology of major depression. The molecules that enhance the level of serotonin either via blocking serotonin reuptake or through inhibition of its metabolism are effective antidepressants. With this as the basis, a group of new molecules that supposedly effect serotoninergic neurotransmission were designed and tested. The new molecular entities (NME-2, NME-5, NME-16 and NME- 24) are active in animal models of behavioral despair. In the present study, the binding of these new NMEs to the serotonin transporter protein (SERT) has been modeled and their activity correlated with the behavioral pattern observed in the mouse forced swim test (FST) model. The putative binding orientations of the NMEs have been identified by docking the molecules into the active site of the SERT. A 3D model of the SERT active site was constructed using comparative protein modeling principles with the X-ray structure of the leucine transporter (LeuT) as template. 3D-QSAR models based on the CoRIA formalism were generated from the experimental data and docking scores for eight novel SERT inhibitors. The CoRIA models highlight the salient features for effective binding of NMEs to the serotonin transporter and are also able to predict pKd values. Based on the significant correlation between the anti-immobility effect seen in the mouse FST study and the binding energies obtained from the docking study along with insights from the interaction patterns with the receptor obtained from the docking, the CoRIA models can be used to suggest structural modifications that can help in optimization of the SERT inhibition. Experimental evidence shows that the NMEs are highly efficacious and could be developed into potential antidepressants.
In the past 20 years, a number of new antiepileptic drugs (AEDs) have been introduced and other molecules are in development, some of which are advantageous in terms of pharmacokinetics, tolerability and potential for drug interactions. These drugs are regarded as second generation compared to older agents such as barbiturates, phenytoin, carbamazepine, ethosuximide and valproic acid. Although some of these second generation compounds may be advantageous in terms of kinetics, tolerability and potential for drug interactions, all of them still target voltage-gated channels or GABA-mediated inhibition, predominantly, without any real improvement in epilepsy therapy. Studies on mechanisms of seizure generation and propagation have identified new potential targets for AEDs. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies. In this review the molecular targets for new AEDs are discussed, providing further suggestions on how future research can be improved.
This study measured the time courses of concentration changes following administration of the catalytic antioxidants Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) and Mn (III) 3-methoxy N, N' bis (salicyclidene) ethylenediamine chloride (EUK-134) in blood and cerebrospinal fluid (CSF) of rats with a spinal cord injury (SCI) and sham controls. Parallel measurements were made for methylprednisolone, the only drug presently used clinically for treating SCI. The time courses kinetically characterized the agents in their stability, disposition, and ability to penetrate the blood-spinal cord barrier (BSB). In both the SCI and control groups, MnTBAP was stable in CSF and in blood across the collection periods (10 h and 24 h, respectively) following administration. In the blood, [EUK-134] and [methylprednisolone] rapidly declined to near basal concentrations at 4 h and 2 h, respectively, post-administration. Therefore the order of stability in CSF and blood was MnTBAP > EUK-134 > methylprednisolone. The maximum CSF/blood concentration ratios for EUK-134, methylprednisolone and MnTBAP post-administration were: 32 ± 3.1%, 19.2 ± 6.4%, and 4.42 ± 0.73% in the injured rats, and 22 ± 6.5%, 17.8 ± 2.9%, and 1.0 ± 0.5% in the sham control animals. This suggests an order of BSB penetration of EUK-134 > methylprednisolone > MnTBAP. Despite much lower penetration by MnTBAP compared with EUK-134 and methylprednisolone, a lower dose of MnTBAP because of its stability provided a higher concentration in CSF than did the other agents given at higher doses. This finding supports further exploration of MnTBAP as a potential treatment for SCI.
Multiple sclerosis (MS) is the most common disabling neurological disease in young adults characterized by recurrent relapses and / or progression that are attributable to multifocal inflammation, demyelination and axonal pathology within the central nervous system. Currently approved disease-modifying treatments achieve their effects primarily by blocking the proinflammatory response in a nonspecific manner. Their limited clinical efficacy urges a more differentiated and specific therapeutic approach. Advances in understanding the pathophysiology of MS and appreciation of the contribution of neurodegenerative processes to disease pathology have led to promising therapeutic approaches at different points along the MS disease pathway: (i) monoclonal antibody therapy has provided the opportunity to rationally direct the therapeutic intervention by specifically targeting mechanisms of the immune system such as CD52 (alemtuzumab), CD25 (daclizumab), VLA-4 (natalizumab) and CD20 (rituximab); (ii) novel oral immunomodulating agents have shown to prevent lymphocyte recirculation from lymphoid organs such as fingolimod (FTY720); (iii) blocking of intracellular signaling cascades or ion channels at the cell-surface can protect axons from degeneration and restore axonal function in experimental settings; (iv) neuroprotective agents and stem cell therapy are able to promote remyelination and axonal regeneration in vitro. Despite the tremendous efforts undertaken, a better understanding of the sequential evolution of the MS lesion and the development of clinical surrogate markers, which allow to define subsets of patients with different forms of underlying pathogenesis, is necessary. This will pave the way for an optimized treatment approach, which will likely need both to target inflammation and to focus on promotion of neuroprotection and repair.
Microglial cells, in contrast to other central nervous system cell types such as neurons and macroglia, are of myeloid origin. They constitute the immune cells of the brain and are involved in neuroinflammatory and neurodegenerative processes. Moreover, diseases of the central nervous system with an inflammatory component are characterized by the migration of bone marrow-derived monocytes into the brain where they differentiate into microglia, the "tissue macrophages" of the nervous system, bearing a therapeutic potential for certain diseases by transplantation of bone marrow-derived hematopoietic stem and progenitor cells. Due to their common origin, microglial cells and monocytes/macrophages share expression of many surface receptors and signalling proteins. Moreover, there is overlap in the expression of many genes related to Alzheimer s disease. Activation of resident and blood-derived microglia in diseases of the central nervous system can be both beneficial, e.g. by degradation of protein aggregates, and detrimental, e.g. by secretion of neurotoxic factors. This review summarizes the current knowledge about the role of microglia in neurodegenerative diseases with a focus on Alzheimer s disease. Moreover, we present data how neuroinflammation is reflected by cellular changes in peripheral blood enabling the use of blood monocytes/macrophages for diagnosis, therapeutic target finding and outcome monitoring of neurodegenerative disorders. In summary, blood monocytes as microglia orthologues are an important model system to study the role of microglia in the pathogenesis of neurodegenerative diseases. They are suitable biomarker targets for diagnosis and prognosis and maybe also therapy of central nervous system disease.
Encephalitis refers to an acute, usually diffuse, inflammatory process affecting the brain. The clinical hallmark of acute encephalitis is the triad of fever, headache, and altered mental status. The most common and important cause of encephalitis is the infection by a virus although other organisms can cause the disease. This article is a general overview of the most common viral encephalitides, divided into two families, Flavivirus and Alphavirus, and provides details about virus and RNA interference. More detailed descriptions of each viral family are provided below.
Ayurveda is a Sanskrit word, which means "the scripture for longevity". It represents an ancient system of traditional medicine prevalent in India and in several other south Asian countries. It is based on a holistic view of treatment which is believed to cure human diseases through establishment of equilibrium in the different elements of human life, the body, the mind, the intellect and the soul [1]. Ayurveda dates back to the period of the Indus Valley civilization (about 3000 B.C) and has been passed on through generations of oral tradition, like the other four sacred texts (Rigveda, Yajurveda, Samaveda and Atharvanaveda) which were composed between 12(th) and 7(th) century B.C [2, 3]. References to the herbal medicines of Ayurveda are found in all of the other four Vedas, suggesting that Ayurveda predates the other Vedas by at least several centuries. It was already in full practice at the time of Buddha (6(th) century B.C) and had produced two of the greatest physicians of ancient India, Charaka and Shushrutha who composed the basic texts of their trade, the Samhitas. By this time, ayurveda had already developed eight different subspecialties of medical treatment, named Ashtanga, which included surgery, internal medicine, ENT, pediatrics, toxicology, health and longevity, and spiritual healing [4]. Ayurvedic medicine was mainly composed of herbal preparations which were occasionally combined with different levels of other compounds, as supplements [5]. In the Ayurvedic system, the herbs used for medicinal purposes are classed as brain tonics or rejuvenators. Among the plants most often used in Ayurveda are, in the descending order of importance: (a) Ashwagandha, (b) Brahmi, (c) Jatamansi, (d) Jyotishmati, (e) Mandukparni, (f) Shankhapushpi, and (g) Vacha. The general appearance of these seven plants is shown in Fig.1. Their corresponding Latin names, as employed in current scientific literature, the botanical families that each of them belongs to, their normal habitats in different areas of the world, as well as the common synonyms by which they are known, are shown in the Table 1. The scientific investigations concerning the best known and most scientifically investigated of these herbs, Ashwagandha will be discussed in detail in this review. Ashwagandha (Withania somnifera, WS), also commonly known, in different parts of the world, as Indian ginseng, Winter cherry, Ajagandha, Kanaje Hindi and Samm Al Ferakh, is a plant belonging to the Solanaceae family. It is also known in different linguistic areas in India by its local vernacular names [6]. It grows prolifically in dry regions of South Asia, Central Asia and Africa, particularly in India, Pakistan, Bangladesh, Sri Lanka, Afghanistan, South Africa, Egypt, Morocco, Congo and Jordon [7]. In India, it is cultivated, on a commercial scale, in the states of Madhya Pradesh, Uttar Pradesh, Punjab, Gujarat and Rajasthan [6]. In Sanskrit, ashwagandha, the Indian name for WS, means "odor of the horse", probably originating from the odor of its root which resembles that of a sweaty horse. The name"somnifera" in Latin means "sleep-inducer" which probably refers to its extensive use as a remedy against stress from a variety of daily chores. Some herbalists refer to ashwagandha as Indian ginseng, since it is used in India, in a way similar to how ginseng is used in traditional Chinese medicine to treat a large variety of human diseases [8]. Ashwagandha is a shrub whose various parts (berries, leaves and roots) have been used by Ayurvedic practitioners as folk remedies, or as aphrodisiacs and diuretics. The fresh roots are sometimes boiled in milk, in order to leach out undesirable constituents. The berries are sometimes used as a substitute to coagulate milk in cheese making. In Ayurveda, the herbal preparation is referred to as a "rasayana", an elixir that works, in a nonspecific, global fashion, to increase human health and longevity. It is also considered an adaptogen, a nontoxic medication that normalizes physiological functions, disturbed by chronic stress, through correction of imbalances in the neuroendocrine and immune systems [9, 10]. The scientific research that has been carried out on Ashwagandha and other ayurvedic herbal medicines may be classified into three major categories, taking into consideration the endogenous or exogenous phenomena that are known to cause physiological disequilibrium leading to the pathological state; (A) pharmacological and therapeutic effects of extracts, purified compounds or multi-herbal mixtures on specific non-neurological diseases; (B) pharmacological and therapeutic effects of extracts, purified compounds or multi-herbal mixtures on neurodegenerative disorders; and (C) biochemical, physiological and genetic studies on the herbal plants themselves, in order to distinguish between those originating from different habitats, or to improve the known medicinal quality of the indigenous plant. Some of the major points on its use in the treatment of neurodegenerative disorders are described below.
This study highlights conformationally controlled mechanistic aspects of peptide inhibitors for BACE 1. Peptide inhibitors with reduced molecular weight tend to have cyclic conformation leading to reduced interactions with catalytic motif. Conformation plays a major role in determining potency of peptide inhibitors. An attempt has been made at designing lead compound with reduced molecular weight along with proper conformation suitable for active site and retention of specificity analogous to natural substrate. Reduced molecular weight should hopefully lead to enhanced bioavailability.
What is the origin of the complex vascular changes that exist in the CNS lesions of Multiple Sclerosis (MS)? From the beginning of the study of the pathological changes in MS in the 19th century, lesions were seen to be associated with veins. On a microscopic level, there have been numerous pathological changes to these vessels including altered structure and permeability, fibrinolysis, iron-related alterations and collagen deposition. Vascular changes in inflammatory conditions outside the CNS are well documented and we hypothesize that angiogenesis (the generation of new blood vessels from existing) is an integral process of lesion development and spread in MS. We demonstrated similar vascular abnormalities in MS and in the animal model, EAE. We measured the increase in angiogenesis-related genes in EAE and review herein the effectiveness of chemical inhibitors of angiogenesis (SU5416, thalidomide and several derivatives). We postulate that interference with angiogenesis provides a suitable non-immunological target for investigation in MS.
Leptomeningeal Carcinomatosis (LC) refers to diffuse seeding of the leptomeninges by tumor metastases and is a rare presentation of solid tumors, particularly breast cancer, lung cancer and malignant melanoma in adults and hematogenous malignancies and primitive neuroectodermal tumor (PNET) in children. Recently, the incidence of LC has been reported to be increasing due to a longer overall survival obtained in patients treated with novel antineoplastic agents. The usual clinical presentation is a multifocal involvement of the neuraxis, with headache and radicular pain being the most common initial symptoms. The most frequent signs are motor deficits, altered mental status and cranial nerve involvement. The treatment of LC remains controversial and no straightforward guidelines exist in the literature. It has a bad prognosis and inevitably fatal outcome despite aggressive therapy.
The insulin-like growth factor-1 (IGF-1) is a pleiotropic factor. Many studies have revealed its importance in the development and maintenance of the central nervous system (CNS). This review will discuss the IGF-1 axis, from the factor itself to the signalling pathways it activates, and its tight regulation. Particular focus will be brought on potential therapeutic targets of the IGF-1 axis in CNS disorders, including brain tumours and neurodegenerative diseases affecting neurons and oligodendrocytes.
Drug delivery to the brain is made difficult by the blood-brain barrier (BBB) which is selectively permeable to organic drug compounds. Several membrane solute and nutrient transporters are expressed in the BBB vasculature, which may be utilized as mechanism of delivery of drugs to the brain. Of interest to us, are the organic cation transporters which could be used to transport cationic compounds into the CNS. In this mini-review, we will review the current understanding of the structural requirements for designing compounds which could effectively use organic cation transporters (OCT). For the first time, structural requirements for both OCT1 and OCT2 versus the BBB choline transporter (BBBCHT) are discussed and compared. The information gained here could increase the success rate in successful CNS drug delivery and therapeutics.
Herbs and spices have been used since ancient times to not only improve the flavor of edible food but also to prevent and treat chronic health maladies. While the scientific evidence for the use of such common herbs and medicinal plants then had been scarce or lacking, the beneficial effects observed from such use were generally encouraging. It is, therefore, not surprising that the tradition of using such herbs, perhaps even after the advent of modern medicine, has continued. More recently, due to an increased interest in understanding the nutritional effects of herbs/spices more comprehensively, several studies have examined the cellular and molecular modes of action of the active chemical components in herbs and their biological properties. Beneficial actions of herbs/spices include anti-inflammatory, anti-oxidant, anti-hypertensive, gluco-regulatory, and anti-thrombotic effects. One major component of herbs and spices is the polyphenols. Some of the aforementioned properties are attributed to the polyphenols and they are associated with attenuating the metabolic syndrome. Detrimental changes associated with the metabolic syndrome over time affect brain and cognitive function. Metabolic syndrome and type-2 diabetes are also risk factors for Alzheimer's disease and stroke. In addition, the neuroprotective effects of herbs and spices have been demonstrated and, whether directly or indirectly, such beneficial effects may also contribute to an improvement in cognitive function. This review evaluates the current evidence available for herbs/spices in potentially improving the metabolic syndrome, as well as their neuroprotective effects on the brain, and cognitive function in animal and human studies.
Dysfunction of serotoninergic neurotransmission is known to be involved in the pathophysiology of major depression. The molecules that enhance the level of serotonin either via blocking serotonin reuptake or through inhibition of its metabolism are effective antidepressants. With this as the basis, a group of new molecules that supposedly effect serotoninergic neurotransmission were designed and tested. The new molecular entities (NME-2, NME-5, NME-16 and NME- 24) are active in animal models of behavioral despair. In the present study, the binding of these new NMEs to the serotonin transporter protein (SERT) has been modeled and their activity correlated with the behavioral pattern observed in the mouse forced swim test (FST) model. The putative binding orientations of the NMEs have been identified by docking the molecules into the active site of the SERT. A 3D model of the SERT active site was constructed using comparative protein modeling principles with the X-ray structure of the leucine transporter (LeuT) as template. 3D-QSAR models based on the CoRIA formalism were generated from the experimental data and docking scores for eight novel SERT inhibitors. The CoRIA models highlight the salient features for effective binding of NMEs to the serotonin transporter and are also able to predict pKd values. Based on the significant correlation between the anti-immobility effect seen in the mouse FST study and the binding energies obtained from the docking study along with insights from the interaction patterns with the receptor obtained from the docking, the CoRIA models can be used to suggest structural modifications that can help in optimization of the SERT inhibition. Experimental evidence shows that the NMEs are highly efficacious and could be developed into potential antidepressants.
In the past 20 years, a number of new antiepileptic drugs (AEDs) have been introduced and other molecules are in development, some of which are advantageous in terms of pharmacokinetics, tolerability and potential for drug interactions. These drugs are regarded as second generation compared to older agents such as barbiturates, phenytoin, carbamazepine, ethosuximide and valproic acid. Although some of these second generation compounds may be advantageous in terms of kinetics, tolerability and potential for drug interactions, all of them still target voltage-gated channels or GABA-mediated inhibition, predominantly, without any real improvement in epilepsy therapy. Studies on mechanisms of seizure generation and propagation have identified new potential targets for AEDs. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies. In this review the molecular targets for new AEDs are discussed, providing further suggestions on how future research can be improved.
This study measured the time courses of concentration changes following administration of the catalytic antioxidants Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) and Mn (III) 3-methoxy N, N' bis (salicyclidene) ethylenediamine chloride (EUK-134) in blood and cerebrospinal fluid (CSF) of rats with a spinal cord injury (SCI) and sham controls. Parallel measurements were made for methylprednisolone, the only drug presently used clinically for treating SCI. The time courses kinetically characterized the agents in their stability, disposition, and ability to penetrate the blood-spinal cord barrier (BSB). In both the SCI and control groups, MnTBAP was stable in CSF and in blood across the collection periods (10 h and 24 h, respectively) following administration. In the blood, [EUK-134] and [methylprednisolone] rapidly declined to near basal concentrations at 4 h and 2 h, respectively, post-administration. Therefore the order of stability in CSF and blood was MnTBAP > EUK-134 > methylprednisolone. The maximum CSF/blood concentration ratios for EUK-134, methylprednisolone and MnTBAP post-administration were: 32 ± 3.1%, 19.2 ± 6.4%, and 4.42 ± 0.73% in the injured rats, and 22 ± 6.5%, 17.8 ± 2.9%, and 1.0 ± 0.5% in the sham control animals. This suggests an order of BSB penetration of EUK-134 > methylprednisolone > MnTBAP. Despite much lower penetration by MnTBAP compared with EUK-134 and methylprednisolone, a lower dose of MnTBAP because of its stability provided a higher concentration in CSF than did the other agents given at higher doses. This finding supports further exploration of MnTBAP as a potential treatment for SCI.
Multiple sclerosis (MS) is the most common disabling neurological disease in young adults characterized by recurrent relapses and / or progression that are attributable to multifocal inflammation, demyelination and axonal pathology within the central nervous system. Currently approved disease-modifying treatments achieve their effects primarily by blocking the proinflammatory response in a nonspecific manner. Their limited clinical efficacy urges a more differentiated and specific therapeutic approach. Advances in understanding the pathophysiology of MS and appreciation of the contribution of neurodegenerative processes to disease pathology have led to promising therapeutic approaches at different points along the MS disease pathway: (i) monoclonal antibody therapy has provided the opportunity to rationally direct the therapeutic intervention by specifically targeting mechanisms of the immune system such as CD52 (alemtuzumab), CD25 (daclizumab), VLA-4 (natalizumab) and CD20 (rituximab); (ii) novel oral immunomodulating agents have shown to prevent lymphocyte recirculation from lymphoid organs such as fingolimod (FTY720); (iii) blocking of intracellular signaling cascades or ion channels at the cell-surface can protect axons from degeneration and restore axonal function in experimental settings; (iv) neuroprotective agents and stem cell therapy are able to promote remyelination and axonal regeneration in vitro. Despite the tremendous efforts undertaken, a better understanding of the sequential evolution of the MS lesion and the development of clinical surrogate markers, which allow to define subsets of patients with different forms of underlying pathogenesis, is necessary. This will pave the way for an optimized treatment approach, which will likely need both to target inflammation and to focus on promotion of neuroprotection and repair.
Microglial cells, in contrast to other central nervous system cell types such as neurons and macroglia, are of myeloid origin. They constitute the immune cells of the brain and are involved in neuroinflammatory and neurodegenerative processes. Moreover, diseases of the central nervous system with an inflammatory component are characterized by the migration of bone marrow-derived monocytes into the brain where they differentiate into microglia, the "tissue macrophages" of the nervous system, bearing a therapeutic potential for certain diseases by transplantation of bone marrow-derived hematopoietic stem and progenitor cells. Due to their common origin, microglial cells and monocytes/macrophages share expression of many surface receptors and signalling proteins. Moreover, there is overlap in the expression of many genes related to Alzheimer s disease. Activation of resident and blood-derived microglia in diseases of the central nervous system can be both beneficial, e.g. by degradation of protein aggregates, and detrimental, e.g. by secretion of neurotoxic factors. This review summarizes the current knowledge about the role of microglia in neurodegenerative diseases with a focus on Alzheimer s disease. Moreover, we present data how neuroinflammation is reflected by cellular changes in peripheral blood enabling the use of blood monocytes/macrophages for diagnosis, therapeutic target finding and outcome monitoring of neurodegenerative disorders. In summary, blood monocytes as microglia orthologues are an important model system to study the role of microglia in the pathogenesis of neurodegenerative diseases. They are suitable biomarker targets for diagnosis and prognosis and maybe also therapy of central nervous system disease.
Encephalitis refers to an acute, usually diffuse, inflammatory process affecting the brain. The clinical hallmark of acute encephalitis is the triad of fever, headache, and altered mental status. The most common and important cause of encephalitis is the infection by a virus although other organisms can cause the disease. This article is a general overview of the most common viral encephalitides, divided into two families, Flavivirus and Alphavirus, and provides details about virus and RNA interference. More detailed descriptions of each viral family are provided below.
Ayurveda is a Sanskrit word, which means "the scripture for longevity". It represents an ancient system of traditional medicine prevalent in India and in several other south Asian countries. It is based on a holistic view of treatment which is believed to cure human diseases through establishment of equilibrium in the different elements of human life, the body, the mind, the intellect and the soul [1]. Ayurveda dates back to the period of the Indus Valley civilization (about 3000 B.C) and has been passed on through generations of oral tradition, like the other four sacred texts (Rigveda, Yajurveda, Samaveda and Atharvanaveda) which were composed between 12(th) and 7(th) century B.C [2, 3]. References to the herbal medicines of Ayurveda are found in all of the other four Vedas, suggesting that Ayurveda predates the other Vedas by at least several centuries. It was already in full practice at the time of Buddha (6(th) century B.C) and had produced two of the greatest physicians of ancient India, Charaka and Shushrutha who composed the basic texts of their trade, the Samhitas. By this time, ayurveda had already developed eight different subspecialties of medical treatment, named Ashtanga, which included surgery, internal medicine, ENT, pediatrics, toxicology, health and longevity, and spiritual healing [4]. Ayurvedic medicine was mainly composed of herbal preparations which were occasionally combined with different levels of other compounds, as supplements [5]. In the Ayurvedic system, the herbs used for medicinal purposes are classed as brain tonics or rejuvenators. Among the plants most often used in Ayurveda are, in the descending order of importance: (a) Ashwagandha, (b) Brahmi, (c) Jatamansi, (d) Jyotishmati, (e) Mandukparni, (f) Shankhapushpi, and (g) Vacha. The general appearance of these seven plants is shown in Fig.1. Their corresponding Latin names, as employed in current scientific literature, the botanical families that each of them belongs to, their normal habitats in different areas of the world, as well as the common synonyms by which they are known, are shown in the Table 1. The scientific investigations concerning the best known and most scientifically investigated of these herbs, Ashwagandha will be discussed in detail in this review. Ashwagandha (Withania somnifera, WS), also commonly known, in different parts of the world, as Indian ginseng, Winter cherry, Ajagandha, Kanaje Hindi and Samm Al Ferakh, is a plant belonging to the Solanaceae family. It is also known in different linguistic areas in India by its local vernacular names [6]. It grows prolifically in dry regions of South Asia, Central Asia and Africa, particularly in India, Pakistan, Bangladesh, Sri Lanka, Afghanistan, South Africa, Egypt, Morocco, Congo and Jordon [7]. In India, it is cultivated, on a commercial scale, in the states of Madhya Pradesh, Uttar Pradesh, Punjab, Gujarat and Rajasthan [6]. In Sanskrit, ashwagandha, the Indian name for WS, means "odor of the horse", probably originating from the odor of its root which resembles that of a sweaty horse. The name"somnifera" in Latin means "sleep-inducer" which probably refers to its extensive use as a remedy against stress from a variety of daily chores. Some herbalists refer to ashwagandha as Indian ginseng, since it is used in India, in a way similar to how ginseng is used in traditional Chinese medicine to treat a large variety of human diseases [8]. Ashwagandha is a shrub whose various parts (berries, leaves and roots) have been used by Ayurvedic practitioners as folk remedies, or as aphrodisiacs and diuretics. The fresh roots are sometimes boiled in milk, in order to leach out undesirable constituents. The berries are sometimes used as a substitute to coagulate milk in cheese making. In Ayurveda, the herbal preparation is referred to as a "rasayana", an elixir that works, in a nonspecific, global fashion, to increase human health and longevity. It is also considered an adaptogen, a nontoxic medication that normalizes physiological functions, disturbed by chronic stress, through correction of imbalances in the neuroendocrine and immune systems [9, 10]. The scientific research that has been carried out on Ashwagandha and other ayurvedic herbal medicines may be classified into three major categories, taking into consideration the endogenous or exogenous phenomena that are known to cause physiological disequilibrium leading to the pathological state; (A) pharmacological and therapeutic effects of extracts, purified compounds or multi-herbal mixtures on specific non-neurological diseases; (B) pharmacological and therapeutic effects of extracts, purified compounds or multi-herbal mixtures on neurodegenerative disorders; and (C) biochemical, physiological and genetic studies on the herbal plants themselves, in order to distinguish between those originating from different habitats, or to improve the known medicinal quality of the indigenous plant. Some of the major points on its use in the treatment of neurodegenerative disorders are described below.
This study highlights conformationally controlled mechanistic aspects of peptide inhibitors for BACE 1. Peptide inhibitors with reduced molecular weight tend to have cyclic conformation leading to reduced interactions with catalytic motif. Conformation plays a major role in determining potency of peptide inhibitors. An attempt has been made at designing lead compound with reduced molecular weight along with proper conformation suitable for active site and retention of specificity analogous to natural substrate. Reduced molecular weight should hopefully lead to enhanced bioavailability.
What is the origin of the complex vascular changes that exist in the CNS lesions of Multiple Sclerosis (MS)? From the beginning of the study of the pathological changes in MS in the 19th century, lesions were seen to be associated with veins. On a microscopic level, there have been numerous pathological changes to these vessels including altered structure and permeability, fibrinolysis, iron-related alterations and collagen deposition. Vascular changes in inflammatory conditions outside the CNS are well documented and we hypothesize that angiogenesis (the generation of new blood vessels from existing) is an integral process of lesion development and spread in MS. We demonstrated similar vascular abnormalities in MS and in the animal model, EAE. We measured the increase in angiogenesis-related genes in EAE and review herein the effectiveness of chemical inhibitors of angiogenesis (SU5416, thalidomide and several derivatives). We postulate that interference with angiogenesis provides a suitable non-immunological target for investigation in MS.
Leptomeningeal Carcinomatosis (LC) refers to diffuse seeding of the leptomeninges by tumor metastases and is a rare presentation of solid tumors, particularly breast cancer, lung cancer and malignant melanoma in adults and hematogenous malignancies and primitive neuroectodermal tumor (PNET) in children. Recently, the incidence of LC has been reported to be increasing due to a longer overall survival obtained in patients treated with novel antineoplastic agents. The usual clinical presentation is a multifocal involvement of the neuraxis, with headache and radicular pain being the most common initial symptoms. The most frequent signs are motor deficits, altered mental status and cranial nerve involvement. The treatment of LC remains controversial and no straightforward guidelines exist in the literature. It has a bad prognosis and inevitably fatal outcome despite aggressive therapy.
The insulin-like growth factor-1 (IGF-1) is a pleiotropic factor. Many studies have revealed its importance in the development and maintenance of the central nervous system (CNS). This review will discuss the IGF-1 axis, from the factor itself to the signalling pathways it activates, and its tight regulation. Particular focus will be brought on potential therapeutic targets of the IGF-1 axis in CNS disorders, including brain tumours and neurodegenerative diseases affecting neurons and oligodendrocytes.

Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed.