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A case-control study was undertaken to investigate the status of platelet monoamine oxidase-B (MAO-B) activity in Indian cases of idiopathic Parkinson's disease. A significant increase in the activity of platelet MAO-B was observed in Parkinson's cases (n = 26) as compared to controls (n = 26). No significant change in the activity of the enzyme was observed while the data was analysed with respect to age, sex and duration of disease. A trend of decrease in platelet MAO-B activity was observed in Parkinson's cases with respect to stage although the change was not significant. No correlation in platelet MAO-B activity was observed with respect to age and sex in the control subjects. Parkinson's cases treated with L-DOPA and MAO-B inhibitor exhibited decreased platelet MAO-B activity as compared to drug naive cases and those treated with L-DOPA alone. Interestingly, Parkinson's cases treated with L-DOPA and amantadine also had lower platelet MAO-B activity as compared to drug naive cases and those treated with L-DOPA alone. Activity of platelet MAO-B in Parkinson's patients was increased in naive cases and those treated with L-DOPA alone or in combination with other drugs compared to controls. The results of the present study indicate that phenotypic activity of platelet MAO-B is high in Indian Parkinson's cases. Further, action mechanism of drugs used in the treatment of Parkinson's disease could be understood by assay of platelet MAO-B activity. It is an interesting observation and may be looked further in large number of cases.

Turmeric has been in use since ancient times as a condiment and due to its medicinal properties. Curcumin, the yellow colouring principle in turmeric, is polyphenolic and major active constituent. Besides anti-inflammatory, thrombolytic and anticarcinogenic activities, curcumin also possesses strong antioxidant property. In view of the novel combination of properties, neuroprotective efficacy of curcumin was studied in rat middle cerebral artery occlusion (MCAO) model. Rats were subjected to 2 h of focal ischemia followed by 72 h of reperfusion. They were pre-treated with curcumin (100 mg/kg, po) for 5 days prior to MCAO and for another 3 days after MCAO. The parameters studied were behavioural, biochemical and histological. Treatment with curcumin could significantly improve neurobehavioral performance compared to untreated ischemic rats as judged by its effect on rota-rod performance and grid walking. A significant inhibition in lipid peroxidation and an increase in superoxide dismutase (SOD) activity in corpus striatum and cerebral cortex was observed following treatment with curcumin in MCAO rats as compared to MCAO group. Intracellular calcium levels were decreased following treatment with curcumin in MCAO rats. Histologically, a reduction in the infarct area from 33% to 24% was observed in MCAO rats treated with curcumin. The study demonstrates the protective efficacy of curcumin in rat MCAO model.

A series of 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines has been synthesized and evaluated for hypotensive activity. The QSAR studies indicate that resonance and hydrophobic parameters of the aryl substituents are important for hypotensive activity. The similar role of resonance parameter in describing the variance of 5-HT(2A) receptor binding affinities of these compounds suggests a possible role of 5-HT(2A) receptors in mediating the hypotensive action of title compounds.

The neuroprotective potential of ethanol:water (1:1) extract of rhizomes of Acorus calamus (AC-002) has been investigated in middle cerebral artery occlusion (MCAO)-induced ischaemia in rats. A significant behavioural impairment in Rota-Rod performance and grid walking was observed in rats, 72 hours after MCAO as compared to sham-operated animals. These rats also exhibited an increase in lipid peroxidation (cortex -157%, corpus striatum - 58%) and a decrease in glutathione levels (cortex - 59%, corpus striatum - 34%) and superoxide dismutase (SOD) activity (cortex - 64%, corpus striatum - 32%) as compared to sham-operated animals. Ischaemic rats treated with AC-002 (25 mg/kg, p.o.) exhibited a significant improvement in neurobehavioural performance viz. Rota-Rod performance and grid walking as compared to the MCAO group. Interestingly, treatment with AC-002 in MCAO rats significantly decreased malonaldialdehyde levels in cortex as compared to ischaemic rats. A significant increase in reduced glutathione levels and SOD activity was also observed both in cortex and corpus striatum in MCAO rats treated with AC-002 in comparison to MCAO rats. Treatment with AC-002 in MCAO rats also reduced the contralateral cortical infarct area (19%) as compared to MCAO rats (33%). Neurological function score was improved in the AC-002-treated rats as compared to the MCAO group. The results of the present study indicate the neuroprotective efficacy of A. calamus in the rat model of ischaemia.

Turmeric (Curcuma longa rhizomes), commonly used as a spice is well documented for its medicinal properties in Indian and Chinese systems of medicine. It has been widely used for the treatment of several diseases. Epidemiological observations, though inconclusive, are suggestive that turmeric consumption may reduce the risk of some form of cancers and render other protective biological effects in humans. These biological effects of turmeric have been attributed to its constituent curcumin that has been widely studied for its anti-inflammatory, anti-angiogenic, anti-oxidant, wound healing and anti-cancer effects. As a result of extensive epidemiological, clinical, and animal studies several molecular mechanisms are emerging that elucidate multiple biological effects of curcumin. This review summarizes the most interesting in vitro and in vivo studies on the biological effects of curcumin.

Smoke Shield is a formulation designed to reduce smoke related mutagenicity and toxicity in the population. Smoke Shield contains a dual extract of turmeric (Curcuma longa) obtained by supercritical CO2 gas extraction and post-supercritical hydroethanolic extraction together with extracts of green tea and other spices, whose presence synergistically increases the activity of turmeric. In the present study we have shown its antimutagenic activity to various environmental mutagens in vitro and in vivo. Smoke Shield was found to produce significant inhibition of mutagenicity to Salmonella typhimurium induced by sodium azide and 4-nitro-0-phenylenediamine (NPD) at a concentration of 2 mg/plate while inhibition to N-methyl-N-nitro N'nitrosoguanidine was less significant. Inhibition was also found to depend upon the strain which was used. Smoke Shield was found to be more effective against mutagens needing metabolic activation such as 2-Acetamidofluorene (2-AAF) and benzo[a]pyrene. Smoke Shield was also found to significantly inhibit the mutagenicity induced by tobacco extract to Salmonella typhimurium TA102. Smoke Shield was also found to inhibit the urinary mutagenicity of rats treated with the benzo[a]pyrene and tobacco extract. Moreover, Smoke Shield administration was found to inhibit the urinary mutagenicity in smokers. These results indicate that Smoke Shield could inhibit mutagenic response in vitro and in vivo produced by several kinds of mutagens present in our atmosphere.

Curcumin (diferuloylmethane), an active ingredient of turmeric, is known to have multiple activities, including an antioxidant property, and has been suggested to be of use in treatment of several diseases. The present study has been undertaken to investigate the protective effect of curcumin against lead-induced neurotoxicity in rats. Exposure of rats to lead (50 mg/kg po) for 45 days caused an increase in lipid peroxidation (LPO) and a decrease in reduced glutathione (GSH) levels in cerebellum, corpus striatum, hippocampus and frontal cortex as compared with controls. Lead levels were significantly increased in these rats. Activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) decreased in all the brain regions following lead exposure. Interestingly, cotreatment with curcumin (100 mg/kg po) and lead (50 mg/kg po) for 45 days caused a significant decrease in LPO with concomitant decrease in lead levels in all the brain regions as compared with those treated with lead alone. A significant increase in reduced glutathione (GSH) levels, SOD and CAT activities was also observed in all the four brain regions in rats simultaneously treated with curcumin and lead. The results suggest that curcumin may prevent lead-induced neurotoxicity.

Objective: The present study was undertaken to investigate the alterations in platelet 5-HT2 receptor binding in patients with tension-type headache., Background: Serotonin (5-HT) has an important but complex role in pain modulation. The involvement of serotonin in tension-type headache has been investigated by studying serotonin in peripheral blood, but results have been inconclusive. There are, however, only a few investigations in which the status of platelet serotonin transporters has been studied by 3H imipramine and 3H paroxetine. The present study was undertaken to investigate alterations in platelet 5-HT2A receptors using 3H ketanserin as a ligand., Methods: Platelet 3H ketanserin binding was studied in 14 patients with tension-type headache and in 15 healthy controls. The binding characteristics, equilibrium dissociation constant and maximal number of binding sites were determined by Scatchard analysis., Results: There was no change in the equilibrium dissociation constant in the patients with headache as compared to the control group, but subgroup analysis revealed that patients with tension-type headache with a headache index of less than 360 had a significantly lower equilibrium dissociation constant as compared to those with a headache index of more than 360; there was a significant correlation between the equilibrium dissociation constant and the headache index. A significant decrease was observed in the maximal number of binding sites in tension-type headache. No correlation was observed between the maximal number of binding sites and age, duration of illness, or headache intensity., Conclusions: The findings of the present study show that there is a decrease in the number of binding sites of 5-HT2A receptors in some patients with tension-type headache, suggesting postsynaptic serotonergic dysfunction and the involvement of serotonin in that group.

Modulation of immune response to alleviate disease has been of interest since long. Plant extracts have been widely investigated for possible immunomodulatory properties. We have evaluated the anticellular and immunomodulatory properties of ethanolic extract of Acorus calamus rhizome. This extract inhibited proliferation of mitogen (phytohaemagglutinin; PHA) and antigen (purified protein derivative; PPD)-stimulated human peripheral blood mononuclear cells (PBMCs). In addition, A. calamus extract inhibited growth of several cell lines of mouse and human origin. It also inhibited production of nitric oxide (NO), interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha). Intracytoplasmic interferon-gamma (IFN-gamma) and expression of cell surface markers, CD16 and HLA-DR, on human PBMC, were not affected on treatment with A. calamus extract but CD25 expression was down regulated. Our study demonstrates the antiproliferative and immunosuppressive potential of ethanolic extract of A. calamus rhizome in vitro., (Copyright 2002 Elsevier Science B.V.)

The antistress effect of bacosides of Brahmi (Bacopa monnieri, BBM), dissolved in distilled water, was -studied in adult male Sprague Dawley rats by administering oral doses of 20 and 40 mg/kg for 7 consecutive days. In half of the animals treated with 20 or 40 mg/kg of BBM, stress was given 2 h after the last dose. Stress was also administered to the animals treated with distilled water alone. BBM, at both doses, did not induce a significant change in the expression of Hsp70 in any brain region studied while stress alone produced a significant increase in the Hsp70 expression in all the brain regions. A significant decrease in the activity of superoxide dismutase (SOD) was evident in the hippocampus with the lower dose of BBM and in animals given stress alone, while an increase in the activity of SOD was observed in the brain regions with the higher dose of BBM. An increase in the activity of cytochrome P450 (P450) dependent 7-pentoxyresorufin-o-dealkylase (PROD) and 7-ethoxyresorufin-o-deethylase (EROD) was observed in all the brain regions after exposure to stress alone and with both doses of BBM although the magnitude of induction of P450 expression was less with a higher dose of BBM. Interestingly, stress when given to the animals pretreated with BBM for 7 days resulted in a decrease in Hsp70 expression in all the brain regions with a significant decrease occurring only in the hippocampus. Likewise the activity of SOD was found to be further reduced in all the brain regions in the animals treated with the lower dose of BBM followed by stress. However, when stress was given to the animals pretreated with the higher dose of BBM, a significant increase in the enzyme activity was observed in the cerebral cortex and in the rest of the brain while the activity of SOD was reduced to a much greater extent in the cerebellum and in the hippocampus. Likewise, the activity of P450 enzymes was found to be restored to almost control levels in the animals given stress and pretreated with the higher dose of BBM, while a lesser degree of induction, compared with animals treated with BBM or stress alone, was observed in the animals pretreated with the lower dose of BBM and given stress. The data indicate that BBM has potential to modulate the activities of Hsp70, P450 and SOD thereby possibly allowing the brain to be prepared to act under adverse conditions such as stress., (Copyright 2002 John Wiley & Sons, Ltd.)

Background: alterations in the polymorphonuclear leukocyte (PMNs) receptors, second messenger system and in their responses have been found associated with depression. Recently role of tetrahydrobiopterin and nitric oxide has also been reported in the depressive disorders. It was therefore considered worthwhile to investigate the NOS activity in the PMNs, which like neurons, also express neuronal NOS (nNOS), antioxidant enzyme levels [superoxide dismutase (SOD), catalase and glutathione peroxidase (Gpx)] and beta-adrenergic receptors in the patients of depression., Methods: patients were diagnosed according to the DSM-IV and were medication free, while healthy age-matched controls were also included in the study to estimate nitrite content, beta-adrenergic receptors and antioxidant enzymes in the PMNs according to the standard methodologies., Results: an analysis of 66 cases of depression and 114 controls revealed 73% decrease in nitrite content and 71% decrease in beta-adrenergic receptor binding in the patients as compared to the healthy controls. However, activities of SOD, catalase and Gpx were not significantly altered in the patients., Conclusion: the results of the present study for the first time indicate alterations the NOS activity in PMNs obtained form the patients of affective disorders.

Extracts of plants have been widely evaluated for possible antiproliferative and anticarcinogenic properties. The antiproliferative activity of ethanolic extract of Boerhaavia diffusa, a plant used in traditional medicine, was evaluated in several cells. It inhibited T cell mitogen phytohemagglutinin and concanavalin A-stimulated proliferation of human peripheral blood mononuclear cells (PBMC). It also inhibited purified protein derivative antigen-stimulated PBMC proliferation and human mixed lymphocyte culture. In addition, B. diffusa extract inhibited the growth of several cell lines of mouse and human origin, such as mouse macrophage cells (RAW 264.7), human macrophage cells (U937), human monocytic cells (THP-1), mouse fibroblast cells (L929), human embryonic kidney cells (HEK293), mouse liver cells (BNLCL.2), African green monkey kidney cells (COS-1), mouse lymphoma cells (EL-4), human erythroleukemic cells (K562), and human T cells (Jurkat). The present study has demonstrated the antiproliferative potential of ethanolic extract of B. diffusa in vitro.

We have earlier reported that ethanolic extract of Boerhaavia diffusa, a plant used in Indian traditional system of medicine, significantly inhibits the cell proliferation. This led us to evaluate the immunomodulatory properties of this plant extract on various in vitro tests such as human natural killer (NK) cell cytotoxicity, production of nitric oxide (NO) in mouse macrophage cells, RAW 264.7, interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), intracytoplasmic interferon-gamma (IFN-gamma) and expression of various cell surface markers on human peripheral blood mononuclear cells (PBMCs). Ethanolic extracts of B. diffusa roots inhibited human NK cell cytotoxicity in vitro, production of NO in mouse macrophage cells, IL-2 and TNF-alpha in human PBMCs. Intracytoplasmic IFN-gamma and cell surface markers such as CD16, CD25, and HLA-DR did not get affected on treatment with B. diffusa extract. Our study demonstrates immunosuppressive potential of ethanolic extract of B. diffusa.

Exposure of rats to acrylamide (ACR) caused hind limb paralysis in 58% of the animals on day 10 and decreased behavioural parameters, namely distance travelled, ambulatory time, stereotypic time and basal stereotypic movements compared with the control group. These rats also had a decrease in the reduced glutathione (GSH) content and glutathione-S-transferase (GST) activity in the corpus striatum and an increase in striatal dopamine receptors, as evident by an increase in the binding of 3H-spiperone to striatal membranes. Treatment with the ethanol:water (1:1) extract of the rhizomes of Acorus calamus (AC-002) increased the GSH content and GST activity in the corpus striatum while insignificant changes were observed in other parameters. Rats treated with ACR and AC-002 in combination had a lower incidence of paralysis (18%) compared with those treated with ACR alone on day 10 of the experiment. The rats also showed a partial recovery in other behavioural parameters. The levels of GSH content and GST activity increased in the corpus striatum, while the dopamine receptors decreased compared with the ACR treated rats. The results suggest that the neurobehavioural changes produced by ACR may be prevented following treatment with Acorus calamus rhizomes.

Rationale: Recent studies have suggested augmentation in the inflammatory response as well as involvement of nitric oxide (NO) in mood disorders. Polymorphonuclear leukocytes (PMN), NO and free radicals have been associated with inflammatory response; however, the status of NO in the PMN has not been investigated so far in schizophrenia patients., Objectives: The present study was undertaken to investigate levels of nitrite (a metabolite of NO), malonaldehyde (MDA, lipid peroxidation product) and antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase (Gpx) in the PMN of schizophrenia patients., Methods: Patients with schizophrenia (n=62) were diagnosed according to DSM-IV and were free of anti-psychotic medications/ECT for at least 3 months. Mean age of the patients was 29.06+/-1.17 years, with a male to female ratio of 4:1, and mean duration of illness was 3.7+/-0.6 years. The control group consisted of 82 healthy subjects with a mean age of 37.0+/-1.26 and a male to female ratio of 5:1. PMN were isolated from the blood. Nitrite, MDA and antioxidant enzymes were estimated by standard biochemical techniques in the PMN of normal healthy controls and schizophrenia patients. Platelet and plasma nitrite levels were also estimated in controls and schizophrenia patients., Results: Nitrite content in the PMN was reduced to 68%, while plasma and platelet nitrite content in schizophrenia patients was not significantly changed in comparison to controls. Malonaldehyde (MDA) content in PMN was significantly augmented in schizophrenia patients but activity of SOD, catalase and Gpx remain unaltered., Conclusion: Results obtained indicate a significant decrease in NO synthesis and an increase in MDA in the PMN of schizophrenia patients, while antioxidant enzyme activities were not altered in the PMN of schizophrenia patients. This suggests that the decrease in PMN NO synthesis by PMN might lead to oxidative stress in schizophrenia patients.

Objective: To investigate blood nitrite levels after migraine attacks and to assess whether or not the change in nitric oxide levels observed during acute migraine persist after the attacks., Background: Involvement of nitric oxide has been suggested in the initiation of acute migraine. Recent studies have shown alteration in the platelet response and platelet nitrite levels during migraine attacks., Methods: Patients with migraine with aura and patients without aura were included in the study. The study was conducted on 50 patients with migraine and 90 healthy controls. Blood from the patients was collected at least 7 +/- 0.8 days after the last attack of migraine. Nitrite levels in the polymorphonuclear leukocytes, platelets, and plasma were estimated. Platelet aggregation response in some of these patients was also studied., Results: No significant change in the polymorphonuclear leukocyte, platelet, and plasma nitrite levels in patients with migraine compared to controls was observed. Patients with migraine with aura had significantly lower polymorphonuclear leukocyte nitrite levels compared to those without aura (P<.05). In addition, no significant difference in the adenosine diphosphate-induced platelet aggregation was observed in the migraineurs compared to the healthy controls., Conclusions: Results obtained indicate that the platelet aggregation response and the blood nitrite levels were not altered significantly after an attack in the patients with migraine.

The present report, describes for the first time the clinical efficacy of curcumin, the active constituent of rhizomes of Curcuma longa, in the treatment of patients suffering from idiopathic inflammatory orbital pseudotumours. Curcumin was administered orally at a dose of 375 mg/3 times/day orally for a period of 6-22 months in eight patients. They were followed up for a period of 2 years at 3 monthly intervals. Five patients completed the study, out of which four recovered completely and in one patient the swelling regressed completely but some limitation of movement persisted. No side effect was noted in any patient and there was no recurrence. It is suggested that curcumin could be used as a safe and effective drug in the treatment of idiopathic inflammatory orbital pseudotumours., (Copyright 2000 John Wiley & Sons, Ltd.)

Protective effects of NOS inhibitors and free radical scavengers in cerebral ischemia are well documented. The present study was undertaken to determine the possible effects of NOS inhibition on brain antioxidants. Levels of both enzymatic [glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD)] and non-enzymatic [reduced glutathione (GSH)] antioxidants following nitric oxide synthase (NOS) inhibition by N(G)-nitro-L-arginine methyl ester (L-NAME), D-NAME or 7-nitroindazole (7-NI) have been investigated. NOS activity and antioxidant levels in the rat cerebellum and medulla were estimated 1 h after treatment with L-NAME (10, 30 and 100 mg/kg, i.p.), D-NAME (100 mg/kg, i.p.) or 7-NI (25 mg/kg, i.p.). L-NAME and 7-NI inhibited NOS activity in a dose-dependent manner. D-NAME also exhibited significant NOS inhibition. The activity of SOD and the GSH level remained unaltered following NOS inhibition. However, L-NAME and D-NAME at 100 mg/kg attenuated GPx activity in the cerebellum, though 7-NI had no effect. L-NAME inhibited catalase activity in medulla only at 30 mg/kg, but had no effect in cerebellum. However, 7-NI (25 mg/kg), D-NAME and L-NAME at 100 mg/kg did not affect catalase activity in the rat brain. Thus, NOS inhibition by the three agents did not have major effects on brain antioxidant levels.

Objective: The present study was undertaken to evaluate the alteration in the peripheral neuronal nitric oxide synthase (NOS) activity in Parkinson's disease patients. Therefore, basal nitrite content in PMNs, platelets and in the plasma of PD and control Indian population were evaluated., Materials and Methods: We estimated nitrite, the nitric oxide (NO) metabolite, in neutrophils (PMNs), platelets and in plasma of control and in L-dopa treated Parkinson's disease (PD) patients. We also measured the activity of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the PMNs., Results: We observed a significant increase in the basal nitrite content in PMNs of PD patients without any alteration in the plasma and platelets. Thus, the change was specific to PMNs. Catalase activity was significantly less in the PMNs of PD patients, but SOD and GPx remained unaltered., Conclusion: Results obtained in the PD patients exhibit an increase in the NOS activity in PMNs. Thus, involvement of NO is suggested in PD.

Centpropazine is a new antidepressant with minimal anticholinergic effects in preclinical animal models. In this study centpropazine has been compared with imipramine in a double blind randomized multicentric study. A total of 159 patients of major depressive disorder (79 in centpropazine group and 80 in imipramine group) from four centres were included in this trial. Each patient was randomised to receive either centpropazine in a dose of 40 to 120 mg per day or imipramine in a dose of 50 to 150 mg per day for a period of six weeks. The antidepressant efficacy of centpropazine was comparable to imipramine but anticholinergic side effects were four times less than imipramine. This establishes centpropazine as an effective antidepressant with remarkably safer tolerability profile.

Curcumin, obtained from rhizomes of Curcuma longa, was administered orally to patients suffering from chronic anterior uveitis (CAU) at a dose of 375 mg three times a day for 12 weeks. Of 53 patients enrolled, 32 completed the 12-week study. They were divided into two groups: one group of 18 patients received curcumin alone, whereas the other group of 14 patients, who had a strong PPD reaction, in addition received antitubercular treatment. The patients in both the groups started improving after 2 weeks of treatment. All the patients who received curcumin alone improved, whereas the group receiving antitubercular therapy along with curcumin had a response rate of 86%. Follow up of all the patients for the next 3 years indicated a recurrence rate of 55% in the first group and of 36% in the second group. Four of 18 (22%) patients in the first group and 3 of 14 patients (21%) in the second group lost their vision in the follow up period due to various complications in the eyes, e.g. vitritis, macular oedema, central venous block, cataract formation, glaucomatous optic nerve damage etc. None of the patients reported any side effect of the drug. The efficacy of curcumin and recurrences following treatment are comparable to corticosteroid therapy which is presently the only available standard treatment for this disease. The lack of side effects with curcumin is its greatest advantage compared with corticosteroids. A double blind multi-centric clinical trial with this drug in CAU is highly desirable to further validate the results of the present study.

Sixteen novel 2-substituted acetyl amino-5-alkyl-1,3,4-thiadiazole were synthesized and screened for their pharmacological activities. A few of the compounds namely 11, 12 and 16 showed anti-inflammatory activities comparable to phenylbutazone. Compound 12 also showed significant non-specific spasmolytic activity. Diuretic activity of compound 15 at a dose level of 90 mg/kg p.o. was two fold higher compared to 50 mg/kg p.o. of furosemide. Comparable diuresis was also produced by compounds 9, 10 and 16.

Pentylenetetrazol (PTZ; 30 mg/kg, i.m.) produced an acute anxiogenic effect on the behaviour of a social colony of rhesus monkeys acclimatized to laboratory conditions. The animals exhibited hypervigilance, aggressiveness, tachypnea, piloerection and frequent change of posture and also had raised plasma cortisol levels. These effects of PTZ were antagonized by benzodiazepines (diazepam; 1 mg/kg, i.v. and alprazolam; 0.05 mg/kg, p.o.). Non-benzodiazepine anxiolytic drug (buspirone; 10 mg/kg, p.o.) blocked the behavioural effects but not the rise in plasma cortisol concentration. On the other hand, pretreatment with hypnosedative (promethazine; 5 mg/kg, i.m.) or anticonvulsant (sodium valproate; 40 mg/kg, p.o.) agents did not attenuate the effects of PTZ indicating the specificity of its anxiogenic response. The model, thus, seems suitable for evaluation of potential anxiolytic agents.

The correlation of brain nitric oxide synthase (NOS) activity with renal hypertension has been investigated in rats. NOS activity was measured by oxyhaemoglobin and by conversion of radioactive arginine to citrulline. There was significant elevation of blood pressure (54% increase) along with left ventricular hypertrophy (26% greater than the control) 8 weeks after coarctation. The brain NOS activity was also significantly reduced in coarctated animals (45% of the control value). Treatment with captopril (angiotensin converting enzyme inhibitor) or centhaquin (centrally acting antihypertensive agent) led to significant reduction of left ventricular hypertrophy and a marked recovery in the brain NOS activity (to 92% and 135% of the control, respectively). Nifedipine (a calcium channel blocker) also brought about normalization of blood pressure but the left ventricular hypertrophy was not prevented. The brain NOS activity in the nifedipine treated group also showed a significant trend of recovery (to 73% of the control NOS activity). The results suggested that there is an inverse correlation between brain NOS activity and blood pressure level., (Copyright 1997 The Italian Pharmacological Society.)

Cyclo(His-Pro) (CHP) has been shown to facilitate cold-induced hypothermia in the desert rat Mastomys natalensis. In the present study, we examined the role of endogenous CHP in hyperthermia induced by hot ambient temperature (40 degrees C) in the above rodent species. The results of these studies show that housing rodents at 40 degrees C resulted in a altered distribution of CHP in the brain, with a rise in hypothalamic content accompanied by an increase in rectal temperature. While administration of exogenous CHP decreased hyperthermia, immunoneutralization of endogenous CHP increased hyperthermia. The results of these studies show that changes in endogenous CHP levels may affect body temperature regulation.

Intraperitoneal administration of fenvalerate, a synthetic pyrethroid, in male rats for 45 days in doses of 100 and 200 mg/kg body weight/day induced hyperexcitability, tremors and paralysis. Tremors were observed after 7 days and gradually reached maxima on 45th day. The symptoms were more marked in rats treated with 200 mg/kg body weight/day. Fenvalerate provoked significant elevation of circulatory thyroid hormones, namely tri-iodothyronine (T3) and thyroxine (T4). A significant increase in total calcium as well as protein-bound calcium in whole brain and hypothalamus were recorded. The elevation of circulatory thyroid hormones as well as the active calcium pool could be together responsible for impairment of motor activity by altering various neuronal processes.

Cerebral microvessels from rats were prepared and characterized by their enrichment of specific markers, namely alkaline phosphatase (AP) and tau-glutamyl transpeptidase (tau-GT). Further, it was observed that AP and tau-GT registered marked increase in aged rats. On the contrary, lactate dehydrogenase (LDH) activity decreased with the increasing age. Monoamine oxidase A activity in the microvessels decreased with age whereas MAO-B moved in the reverse direction. No noticeable change was seen in acetyl-cholinesterase activity with increasing age of rats.

The role of nitric oxide (NO), a well known vasodilator, in the regulation of blood-brain barrier (BBB) permeability is not clear. Therefore, the present study was planned to assess the role of NO-releasing compounds like sodium nitroprusside (SNP) and the active metabolite of molsidomine, SIN-1, as well as a precursor on NO, L-arginine, on this physiological barrier. The permeability was assessed by using several tracers. All three agents increased the permeability of BBB to the tracer. The increase in permeability caused by L-arginine was not blocked by N-nitro-L-arginine methyl ester (L-NAME). L-Arginine-treated brains did not show an elevation of nitrite content, thus ruling out the possibility of NO generation and its involvement in BBB permeability alteration. It is concluded that NO itself causes an increase in the permeability of BBB. However, arginine-induced opening is not NO mediated.

The objective of the present investigation was to study the involvement of NO in regulating the permeability of the blood-brain barrier (BBB) during infections, since NOS is known to be induced following infections. The administration of inactivated Escherichia coli (a source of lipopolysaccharide) or poly (I:C), an interferon inducer, to rats increased the permeability of BBB significantly. This increase was found to be potentiated in the presence of L-arginine, a substrate for NOS, while D-arginine had no such effect. N-nitro L-arginine methyl ester, an inhibitor of NOS, and dexamethasone, an inhibitor of NOS induction, blocked the E. coli-induced effects. These results suggest that during infections, NOS inductions causes the release of large quantities of NO, resulting in increased BBB permeability.

Gamma-HCH (lindane) administered for long durations is reported to cause toxic cardiovascular effects. Present study was carried out to assess the changes in cardiovascular activity and cellular calcium homeostatic mechanisms in rats administered 3 mg kg-1 day-1 of gamma-HCH p.o. for 6 weeks. The changes in electrocardiogram were marked by a decrease in R-R interval and the amplitude of the P wave by 53% and 50%, respectively. The amplitude of R and T waves was increased by 65% and 58%, respectively. Calcium-45 influx was increased in atrial trabeculae (33%) and in papillary muscle (10%). The plasma calcium concentration was increased (32%) and Ca,K-ATPase activity in heart was decreased (50%). It is suggested on the basis of these findings that cellular calcium homeostatic mechanisms are involved in the cardiovascular effects of gamma-HCH administered chronically in rats.

Acute administration of cyclo (His-Pro) to rats cause a dose-dependent decrease in ethanol-induced hypothermia. Bromination of the imidazole moiety of histidine in cyclo (His-Pro) resulted in a significant increase in its potency to attenuate ethanol hypothermia. In contrast, benzylation of the imidazole moiety of histidine or the substitution of one or both of the amino acids in cyclo(His-Pro) led to a total loss of its thermomodulatory activity. In conclusion, it appears from these preliminary data that it may be possible to design analogs of CHP that may be effective antagonists for ethanol hypothermia.

A new met-enkephalin analogue (compound 82/205) was evaluated for its opioidergic activity in mice. The compound showed antinociception (warm water tail-flick test), tolerance, cross tolerance to morphine and physical dependence. The time course of antinociceptive effect of the compound was comparable to morphine. The antinociceptive ED50 (mumol kg-1, i.p.) values for the compound and morphine base were 5.31 and 7.59, respectively. Its antinociceptive effect was blocked by naloxone, beta-FNA (mu antagonist) and naloxonazine (mu1 antagonist) but not by ICI 174,864 (delta antagonist). Naloxone precipitated withdrawal jumpings were 2.6 times less in compound 82/205 treated mice than the morphine treated group. The new analogue compound 82/205 is a potent mu agonist antinociceptive with a possible weak dependence liability.

Eighteen Schiff Bases of 3-amino-2-methylquinazolin-4(3H)-ones were synthesised and screened for anti-inflammatory and diuretic activity. Anti-inflammatory activity was identified in PNG-1, PNG-13, PNG-14, PNG-15 and PNG-17.

Levels of certain antioxidants namely reduced glutathione (GSH), ascorbic acid (Vit C), alpha-tocopherol (Vit E) and antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were compared in monkey and rat brain microvessels which constitute the blood-brain barrier (BBB). The BBB of both the species contains appreciable amounts of the antioxidants to protect against oxidative damage. The level of protection in rat seems to be more efficient than monkey since rat microvessels contain higher concentrations of some of the bio-antioxidants. The comparative status of enzymatic and non-enzymatic protective system against oxidation in the brain microvessels has been discussed.

Effect of myocardial ischaemia on the bioantioxidants levels in the cat heart was evaluated. In addition, effect of curcumin, an anti-inflammatory and anti-thrombotic drug, and quinidine, a standard antiarrhythmic drug, was also studied in the cat. Myocardial ischaemia was induced by the ligation of left descending coronary artery. Quinidine (1 mg/kg, iv) was administered 15 min prior to while curcumin (100 mg/kg, ip) was given 30 min before ligation. Hearts were removed 4 h post coronary artery ligation. Levels of glutathione (GSH), malonaldelhyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT) and lactate dehydrogenase (LDH) were estimated in the ischaemic and non-ischaemic zones. Both the drugs protected the animals against decrease in the heart rate and blood pressure following ischaemia. In the ischaemic zone, after 4 h of ligation, an increase in the level of MDA and activities of MPO and SOD (cytosolic fraction) were observed. Quinidine and curcumin pretreatment prevented the ischaemia-induced elevation in MDA contents and LDH release. Curcumin pretreatment did not prevent the increase in MPO activity while quinidine did. Results obtained indicate alterations in the bioantioxidants following ischaemia and both curcumin and quinidine prevented ischaemia induced changes in the cat heart.

Compound 88-765 (4-amino-6-methylthio-1-(2', 2'-diethoxyethyl)-1 H-pyrazolo[3, 4-d]pyrimidine) has shown potent antiallergic activity in experimental models. The compound inhibited the passive cutaneous anaphylaxis (PCA) reaction in rats in dose-dependent manner (5-100 mg/kg, po) by 47 to 87%. In mice it inhibited PCA by 78% at 50 mg/kg, po. It also inhibited mast cell degranulation of normal and passively sensitised rats induced by compound 48/80 and egg albumin, respectively. These effects of Compound 88-765 were comparable with that of disodium cromoglycate (DSCG). The results suggest that compound 88-765 possesses potent antiallergic activity.