R. C. Srimal

Cadmium-induced alterations in blood- brain barrier permeability and its possible correlation with decreased microvessel antioxidant potential in rat

1 Male albino rats of 21 days age were exposed to 10 p.p.m. cadmium (CdCl2 salt) in drinking water, ad libitum, for 90 days. It increased the brain cadmium levels by 76% (P < 0.05) and 165% ( P < 0.001) respec tively at 30 and 90 days of exposure compared to controls. 2 Cadmium increased blood - brain barrier permeability of fluoroscein dye (24%, P < 0.02) and the levels ofbrain microvessel malondialdehyde (31%, P<0.01) at 90 days of exposure. However, these parameters did not alter significantly at 30 days of exposure. 3 Increased activities of microvessel superoxide dismu tase (18%, P<0.02), glutathione peroxidase (20%, P<0.01) and catalase (28%, P<0.01) were observed at 30 days of exposure. 4 The continuation of the Cd treatment for 90 days decreased the levels of superoxide dismutase (30%, P<0.001), glutathione peroxidase (23%, P<0.005), catalase (25%, P < 0.005), glutathione reductase (18%, P < 0.02), vitamin E (20%, P < 0.01), glutathione (26%, P < 0.01), ascorbic acid (18%, P < 0.05) and ceruloplas min (13%, P<0.05) in the microvessal preparation compared to controls. 5 It appears that Cd-induced blood-brian barrier dysfunction may be related to the depletion of microvessel antioxidant substances along with in crease in lipid peroxidation at 90 days of exposure.

Efficacy of Curcumin in the Management of Chronic Anterior Uveitis

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.

Protective effect of curcumin against lead neurotoxicity in rat.

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.

Nitrite content and antioxidant enzyme levels in the blood of schizophrenia patients

Abstract.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.

Role of curcumin in idiopathic inflammatory orbital pseudotumours

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

Neuroprotective effect of Acorus calamus against middle cerebral artery occlusion-induced ischaemia in rat.

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.

Evidence for the involvement of histamine in the regulation of blood-brain barrier permeability.

Role of histaminergic mechanisms in the regulation of blood-brain barrier (BBB) was assessed in dog. Histamine increased the entry of sodium fluorescein from the blood to the cerebrospinal fluid (CSF) in a dose-dependent manner. Histamine receptor antagonists, mepyramine (H1) and metiamide (H2) per se did not affect the entry of dye in the CSF. Mepyramine failed to affect the change induced by histamine whereas metiamide completely blocked the histamine-induced entry of sodium fluorescein in CSF. 2-Methyl histamine, a specific H1-agonist, did not affect the barrier permeability. However, 4-methyl histamine, a specific H2 receptor agonist significantly increased the permeability of BBB. This increase was blocked by metiamide. Forskolin, a stimulant of adenylate cyclase, also increased the entry of dye in the CSF which could be significantly blocked by metiamide. It is concluded that histamine increases the permeability of BBB by affecting H2-receptors linked to adenylate cyclase.

Blood Nitrite Levels in Patients With Migraine During Headache‐Free Period

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.

Neutrophil-Free Radical Generation and Enzymatic Antioxidants in Migraine Patients

The present study was undertaken to elucidate the role of circulating neutrophils if any in oxidative stress in migraine by evaluating free radical generation and activities of enzymatic antioxidants in the blood in 55 patients with migraine and 60 healthy controls. Free radical generation was assessed by flow cytometry, while activity of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) was estimated in blood polymorphonuclear neutrophils (PMNs) by standard procedures. Platelet SOD was also measured. No significant change was found in free radical generation and in the activity of catalase, SOD and GPx in migraine patients. Univariate analysis of PMN catalase level revealed that migraineurs with a positive family history had significantly lower catalase activity compared with those with a negative family history. No correlation was found in the activity of antioxidant enzymes with age, duration of disease, time since last attack and headache index. The platelet SOD also did not show any significant change in patients of migraine without aura. Platelet aggregation in the presence or absence of PMNs was also not altered significantly. Thus the findings of the present study suggest that neutrophils are not the cause of oxidative stress observed in migraine patients.

A PRIMATE MODEL OF ANXIETY

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.