Parkinson's disease: genetics and beyond.

Parkinson's disease (PD) is characterized clinically by resting tremor, rigidity, bradykinesia and postural instability due to progressive and selective loss of dopamine neurons in the ventral substantia nigra, with the presence of ubiquitinated protein deposits called Lewy bodies in the neurons. The pathoetiology of cell death in PD is incompletely understood and evidence implicates impaired mitochondrial complex I function, altered intracellular redox state, activation of proapoptotic factors and dysfunction of ubiquitinproteasome pathway. Now it is believed that genetic aberration, an environmental toxin or combination of both leads to a cascade of events culminating in the destruction of myelinated brainstem catecholaminergic neurons. Also the role of production of significant levels of abnormal proteins, which may misfold, aggregate and interfere with intracellular processes causing cytotoxicity has recently been hypothesized. In this article, the diverse pieces of evidence that have linked the various factors responsible for the pathophysiology of PD are reviewed with special emphasis to various candidate genes and proteins. Furthermore, the present therapeutic strategies and futuristic approaches for the pharmacotherapy of PD are critically discussed.

Migraine: current therapeutic targets and future avenues.

Migraine is characterized by attacks of intense pulsatile and throbbing headache, typically unilateral in nature with or without aura. Migraine affects a substantial fraction (10-20 %) of the world population (more women than men). With regard to the pathophysiology of migraine, several theories have been proposed; the major three are vascular (due to cerebral vasodilatation), neurological (abnormal neurological firing) and neurogenic dural inflammation (release of inflammatory neuropeptides). The drugs used to treat migraine can be divided into two groups: agents that abolish the acute migraine headache and agents aimed at prevention. The acutely acting antimigraine agents (5-HT(1B/1D) receptor agonists) stimulated research interest in the field of migraine. Currently prophylactic treatments for migraine include calcium channel blockers, 5-HT(2) receptor antagonists, beta-adrenoceptor blockers and gamma-amino butyric acid (GABA) agonists. Unfortunately, many of these treatments are non-specific and not always effective. Despite progress, the complex etiology of migraine requires further research, the condition often remains undiagnosed and available therapies are underused. In this review, the evidence that linked the different theories of migraine with its pathophysiology is considered. Furthermore, the present therapeutic targets and future approaches for the acute and prophylactic treatment of migraine are critically evaluated.

Antipsychotic induced metabolic abnormalities: an interaction study with various PPAR modulators in mice.

Abnormalities in glucose and lipid regulation have been reported in schizophrenia during antipsychotic medications. The objectives of the present study were to evaluate the effect of various peroxisome proliferator-activated receptor modulators viz. glimepiride, rosiglitazone and fenofibrate on chlorpromazine, clozapine and ziprasidone induced hyperglycemia and hyperlipidemia in mice. Male Swiss albino mice were orally treated with chlorpromazine, clozapine and ziprasidone concurrently with the antidiabetic medications for 7 days. Plasma glucose, insulin and triglyceride levels were determined at the end of the study. Chlorpromazine and clozapine elevated the glucose and triglyceride levels in normal mice, with no effect on insulin but ziprasidone increased the basal triglyceride and insulin levels and did not have any effect on glucose. Glimepiride and rosiglitazone showed beneficial glucose and triglyceride lowering effects in chlorpromazine and clozapine animals and no effect on insulin levels. Fenofibrate significantly reduced the glucose levels only in animals treated with clozapine, and exhibited significant reduction of triglyceride levels in chlorpromazine, clozapine and ziprasidone treated animals. All three antidiabetic/hypolipidemic agents lowered triglyceride and insulin levels in ziprasidone treated animals. The results of the present studies suggest that hyperglycemia, hyperinsulinemia and hypertriglyceridemia induced by various antipsychotics may involve diverse mechanisms.

GLP-1 based therapy for type 2 diabetes.

Type 2 diabetes mellitus is a major and growing health problem throughout the world. Current treatment approaches include diet, exercise, and a variety of pharmacological agents including insulin, biguanides, sulfonylureas and thiazolidinediones. New therapies are still needed to control metabolic abnormalities, and also to preserve beta-cell mass and to prevent loss of beta-cell function. Glucagon-like peptide 1 (GLP-1) is a drug candidate which potentially fulfils these conditions. GLP-1 is an incretin hormone secreted by intestinal L-cells in response to meal ingestion is a novel pharmacological target with multiple antihyperglycemic actions. GLP-1 glucoregulatory actions include glucose-dependent enhancement of insulin secretion, inhibition of glucagon secretion, slowing of gastric emptying and reduction of food intake. GLP-1 is rapidly inactivated by amino peptidase, dipeptidyl peptidase IV (DPP-IV) and the utility of DPP-IV inhibitors are also under investigation. There is a recent upsurge in the development of GLP-1 mimetics and DPP-IV inhibitors as potential therapy for type 2 diabetes. However, both the strategies are having their own advantages and limitations. The present review summarizes the concepts of GLP-1 based therapy for type 2 diabetes and the current preclinical and clinical development in GLP-1 mimetics and DPP-IV inhibitors. Further, the potential advantages and the limitations of both the strategies are discussed.

Migraine: current concepts and emerging therapies.

Migraine is a recurrent incapacitating neurovascular disorder characterized by attacks of debilitating pain associated with photophobia, phonophobia, nausea and vomiting. Migraine affects a substantial fraction of world population and is a major cause of disability in the work place. Though the pathophysiology of migraine is still unclear three major theories proposed with regard to the mechanisms of migraine are vascular (due to cerebral vasodilatation), neurological (abnormal neurological firing which causes the spreading depression and migraine) and neurogenic dural inflammation (release of inflammatory neuropeptides). The modern understanding of the pathogenesis of migraine is based on the concept that it is a neurovascular disorder. The drugs used in the treatment of migraine either abolish the acute migraine headache or aim its prevention. The last decade has witnessed the advent of Sumatriptan and the 'triptan' class of 5-HT1B/1D receptor agonists which have well established efficacy in treating migraine. Currently prophylactic treatments for migraine include calcium channel blockers, 5-HT2 receptor antagonists, beta adrenoceptor blockers and gamma-amino butyric acid (GABA) agonists. Unfortunately, many of these treatments are non specific and not always effective. Despite such progress, in view of the complexity of the etiology of migraine, it still remains undiagnosed and available therapies are underused. In this article, the diverse pieces of evidence that have linked the different theories of migraine with its pathophysiology are reviewed. Furthermore, the present therapeutic targets and futuristic approaches for the acute and prophylactic treatment of migraine, with a special emphasis to calcitonin gene-related peptide, are critically evaluated.

Effect of Sapindus trifoliatus on hyperalgesic in vivo migraine models.

Phytotherapies have offered alternative sources of therapy for migraine and gained much importance in prophylactic treatment. Sapindus trifoliatus is a medium-sized deciduous tree growing wild in south India that belongs to the family Sapindaceae. The pericarp is reported for various medicinal properties. A thick aqueous solution of the pericarp is used for the treatment of hemicrania, hysteria or epilepsy in folklore medicine. We have investigated the antihyperalgesic effects of the lyophilized aqueous extract of S. trifoliatus in animal models predictive of experimental migraine models using morphine withdrawal-induced hyperalgesia on the hot-plate test and on 0.3% acetic acid-induced abdominal constrictions in adult male Swiss albino mice. The extract significantly (N = 10, P < 0.05) increased the licking latency in the hot-plate test when administered i.p. at 10 mg/kg (6.70 +/- 0.39 s in saline control vs 18.76 +/- 0.96 s in S. trifoliatus-treated animals) and significantly (N = 10, P < 0.001) reduced the abdominal constrictions when administered i.p. at 2 and 10 mg/kg (40.20 +/- 1.36 in saline control vs 30.20 +/- 1.33 and 23.00 +/- 0.98 for 2 and 10 mg/kg, i.p., respectively, in S. trifoliatus-treated animals). Furthermore, when administered i.p. at 20 and 100 mg/kg, the extract significantly (N = 10, P < 0.05) inhibited the apomorphine-induced climbing behavior in mice (climbing duration 15.75 +/- 5.0 min for saline control vs 11.4 +/- 1.28 and 3.9 +/- 1.71 min for 20 and 100 mg/kg, respectively, in S. trifoliatus-treated animals). In receptor radioligand-binding studies, the extract exhibited affinity towards D2 receptors. The findings suggest that dopamine D2 antagonism could be the mechanism involved in the antihyperalgesic activity of the aqueous extract of S. trifoliatus.

Pharmacological studies of the aqueous extract of Sapindus trifoliatus on central nervous system: possible antimigraine mechanisms.

The aqueous extract of pericarp of fruits of Sapindus trifoliatus (ST) Linn., family Sapindaceae was evaluated for its potential effects on central nervous system in mice. The extract at doses 20 and 100 mg/kg, i.p. significantly (p < 0.001) reduced the spontaneous locomotor activity and at 100 mg/kg, increased the thiopental-induced sleeping time. In rota-rod motor co-ordination test, ST at 100 mg/kg, i.p. significantly (p < 0.05-0.01) reduced the endurance time. Further ST exhibited no protection against maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced convulsions in mice. In receptor radioligand binding studies, ST exhibited affinity towards dopaminergic, alpha-adrenergic and muscarnic receptors. The findings suggest that, ST may possess principles with potential neuroleptic properties.

Investigations into the antinociceptive activity of Sapindus trifoliatus in various pain models.

The effect of the aqueous extract of Sapindus trifoliatus (ST) on chemical, thermal-induced pain, nitroglycerin-induced hyperalgesia and pain on inflamed tissue was investigated. The extract (20 and 100 mg x kg(-1), i.p.) significantly inhibited acetic-acid-induced abdominal constrictions, formalin-induced pain licking and hotplate-induced pain in mice. Furthermore, the extract significantly increased the response latencies of nitroglycerin-induced hyperalgesia by the tail-flick method and mechanical pain on carrageenan-induced inflamed paw in rats. The data suggest that ST has an inhibitory activity on both peripheral and central pain mechanisms and has a modulatory role in NO-mediated nociceptive transmission.

In vitro pharmacological investigations of Sapindus trifoliatus in various migraine targets.

Phytotherapies have offered alternative sources of therapy for migraine and gained much importance in prophylactic treatment. The aqueous extract of pericarp of fruits of Sapindus trifoliatus Linn (ST), family Sapindaceae was evaluated for its affinity for 5-HT(1B/1D) receptors in rabbit saphenous vein, alpha-adrenoceptors in rabbit aorta, GABA receptors in guinea pig ileum, 5-HT(2B) receptors in rat fundus and vanilloid receptors in guinea pig trachea. The calcium blocking effect was studied in rabbit aorta while the modulatory role of ST on platelet serotonin release was evaluated in human platelets. The aqueous extract of Sapindus trifoliatus exhibited significant 5-HT(2B) receptor inhibition and moderate platelet serotonin release inhibition.

5-HT3 receptors in selective animal models of cognition.

Role of 5-HT3 receptors in cholinergic hypofunctional models of cognitive impairment in the elevated plus maze model and a passive avoidance model is studied. Cognitive impairment was caused by scopolamine (1 mg/kg, ip) in mice and 5-HT3 ligands mCPBG (1 and 5 mg/kg, ip) and ondansetron (0.5 and 5 mg/kg, ip) were administered before the pre-learning phase to study the effects on acquisition, while post-learning administration was used to determine the effects on consolidation. Ondansetron improved acquisition and retention in cholinergic hypofunctional models while mCPBG potentiated selected impaired cognitive indices. The results indicate the role of 5-HT3 receptors in cognition and that an ideal evaluation of 5-HT3 ligands in cognition should distinguish true cognitive effects from locomotor, motivational and emotional effects.

Preliminary mechanistic studies on the smooth muscle relaxant effect of hydroalcoholic extract of Curcuma caesia.

BACKGROUND AND OBJECTIVES: Curcuma caesia (family Zingiberaceae) is widely used in India as both an anti-inflammatory and anti-asthmatic in Ayurvedic medicine. However, there are no published pharmacological data on Curcuma caesia on its potential anti-asthmatic activity. Hence, the objective of the present investigation is to study the mechanisms by which the hydroalcoholic extract of Curcuma caesia relaxes the smooth muscle in the bronchioles and vasculature of the respiratory tract. METHODS: The hydroalcoholic extract of Curcuma caesia (CC extract) was tested for its per se relaxant effect in guinea pig trachea and also in the presence of various receptor antagonists and enzyme inhibitors namely propranalol, 2', 5'-dideoxyadenosine, methylene blue, glibenclamide, N(omega)-nitro-L-arginine (L-NNA) and alpha-chymotrypsin. Furthermore, the possible role of hydroalcoholic extract in calcium channel modulation was investigated in depolarized rabbit aorta. RESULTS: The CC extract concentration dependently relaxed the carbachol (1 microM)-induced pre-contractions; the IC50 value was found to be 239.36 microg/ml and the incubation of either receptor antagonists or enzyme inhibitors did not exhibit any effect on the relaxation. In the isotonic Ca2+-free high-K+ (60 mM) depolarized aorta, CC extract (30 microg/ml) inhibited concentration-response curves of cumulative Ca2+ (0.1-30 mM) and the PD'2 value was found to be 4.11 microg/ml. INTERPRETATION AND CONCLUSION: The extract showed a dose-dependent, non-specific relaxation of pre-contracted isolated guinea pig trachea. The non-specific relaxant effect of the extract may be due to its ability to modulate calcium activity.

Effect of Sapindus trifoliatus on hyperalgesic in vivo migraine models

Phytotherapies have offered alternative sources of therapy for migraine and gained much importance in prophylactic treatment. Sapindus trifoliatus is a medium-sized deciduous tree growing wild in south India that belongs to the family Sapindaceae. The pericarp is reported for various medicinal properties. A thick aqueous solution of the pericarp is used for the treatment of hemicrania, hysteria or epilepsy in folklore medicine. We have investigated the antihyperalgesic effects of the lyophilized aqueous extract of S. trifoliatus in animal models predictive of experimental migraine models using morphine withdrawal-induced hyperalgesia on the hot-plate test and on 0.3 percent acetic acid-induced abdominal constrictions in adult male Swiss albino mice. The extract significantly (N = 10, P < 0.05) increased the licking latency in the hot-plate test when administered ip at 10 mg/kg (6.70 ± 0.39 s in saline control vs 18.76 ± 0.96 s in S. trifoliatus-treated animals) and significantly (N = 10, P < 0.001) reduced the abdominal constrictions when administered ip at 2 and 10 mg/kg (40.20 ± 1.36 in saline control vs 30.20 ± 1.33 and 23.00 ± 0.98 for 2 and 10 mg/kg, ip, respectively, in S. trifoliatus-treated animals). Furthermore, when administered ip at 20 and 100 mg/kg, the extract significantly (N = 10, P < 0.05) inhibited the apomorphine-induced climbing behavior in mice (climbing duration 15.75 ± 5.0 min for saline control vs 11.4 ± 1.28 and 3.9 ± 1.71 min for 20 and 100 mg/kg, respectively, in S. trifoliatus-treated animals). In receptor radioligand-binding studies, the extract exhibited affinity towards D2 receptors. The findings suggest that dopamine D2 antagonism could be the mechanism involved in the antihyperalgesic activity of the aqueous extract of S. trifoliatus.