SEW2871 reduces seizures via the sphingosine 1-phosphate receptor-1 pathway in the pentylenetetrazol and phenobarbitone kindling model of drug-refractory epilepsy.

Epilepsy is a prevalent neurological disorder characterized by neuronal hypersynchronous discharge in the brain, leading to central nervous system (CNS) dysfunction. Despite the availability of anti-epileptic drugs (AEDs), resistance to AEDs is the greatest challenge in treating epilepsy. The role of sphingosine-1-phosphate-receptor 1 (S1PR1) in drug-resistant epilepsy is unexplored. This study investigated the effects of SEW2871, a potent S1PR1 agonist, on a phenobarbitone (PHB)-resistant pentylenetetrazol (PTZ)-kindled Wistar rat model. We measured the messenger ribonucleic acid (mRNA) expression of multi-drug resistance 1 (MDR1) and multi-drug resistance protein 5 (MRP5) as indicators for drug resistance. Rats received PHB + PTZ for 62 days to develop a drug-resistant epilepsy model. From day 48, SEW2871 (0.25, 0.5, 0.75 mg/kg, intraperitoneally [i.p.]) was administered for 14 days. Seizure scoring, behaviour, oxidative markers like reduced glutathione, catalase, superoxide dismutase, inflammatory markers like interleukin 1 beta tumour necrosis factor alpha, interferon gamma and mRNA expression (MDR1 and MRP5) were assessed, and histopathological assessments were conducted. SEW2871 demonstrated dose-dependent improvements in seizure scoring and neurobehavioral parameters with a reduction in oxidative and inflammation-induced neuronal damage. The S1PR1 agonist also downregulated MDR1 and MRP5 gene expression and significantly decreased the number of dark-stained pyknotic nuclei and increased cell density with neuronal rearrangement in the rat brain hippocampus. These findings suggest that SEW2871 might ameliorate epileptic symptoms by modulating drug resistance through downregulation of MDR1 and MRP5 gene expression.

Novel therapeutic mechanism of action of metformin and its nanoformulation in Alzheimer's disease and role of AKT/ERK/GSK pathway.

INTRODUCTION: Brain Insulin-resistance plays a critical role in pathogenesis of Alzheimer's disease (AD). Current study explored the therapeutic mechanism of metformin (insulin sensitizer) and its solid-lipid nanoformulation (SLN) in rat-model of AD. In our study, SLN was prepared using microemulsion method. AD was induced with ICV-Aß whereas the control-group (sham) received ICV-NS. Treatment arms included, disease-control (no treatment), Metformin (50 mg/kg, 100 mg/kg and 150 mg/kg), SLN-metformin 50 mg/kg and memantine 1.8 mg/kg (positive-control). Animals were tested for cognitive performance (EPM, MWM) after 21 days of therapy and sacrificed. Aß (1-42), hyperphosphorylated tau, pAKTser473, GSK-3ß, p-ERK (ELISA), metformin level(HPLC), neuronal injury score(H&E), Bcl2 and Bax(IHC) was evaluated in isolated brain. In our study, metformin-SLN were of spherical shape (size<200 nm) with 94.08% entrapment efficiency. Metformin was detectable in brain. Compared to sham, the disease-control group showed significantly higher (p ≤ 0.05) memory impairment(MWM and EPM), hyperphosphorylated tau, Aß(1-42), neuronal-injury, Bax and lower Bcl-2 expression. Treatment with metformin and nanoformulation significantly reverse these parameters. AKT-ERK-GSK3ß-Hyperphosphorylated tau pathway was found to be involved in the protective efficacy of metformin. To conclude, both metformin and its SLN were found to be effective as therapeutic agents in AD which act through the AKT-ERK-GSK3ß-Hyperphosphorylated tau pathway. We need population based studies to confirm the same.

A randomized controlled trial comparing the efficacy, tolerability, and cost of oral iron preparations in iron-deficiency anemia in pregnancy.

OBJECTIVE: To evaluate the efficacy, tolerability, and cost of four commonly prescribed oral iron preparations: ferrous sulfate (FS), ferrous fumarate (FF), ferrous ascorbate (FA), and carbonyl iron (CI) in the treatment of iron-deficiency anemia (IDA) in pregnant women. METHODS: It was a prospective, randomized, open-label, blinded endpoint (PROBE) design with four parallel active control groups: FS, FF, FA, CI. The primary outcome was the proportion of participants becoming non-anemic (Hb ≥ 11 g%) at the end of the study period. The secondary outcomes were the proportion of participants achieving normal red blood corpuscular indices such as mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration; the proportion of participants achieving normal iron indices such as serum iron, serum ferritin, total iron-binding capacity, and transferrin saturation; and comparison of incidence of any adverse events between treatment groups and comparison of costs of individual drug therapy between treatment groups. RESULTS: One hundred and twenty patients were randomized to four different groups (n = 30). The results of the present study show that all the four iron salts at the dose of 200 mg elemental iron per day were equally effective in improving hemoglobin concentration and other hematological parameters. The adverse effects were more common in the FF group (56.7%). The pharmacoeconomic analysis showed that all the drugs are equally cost-effective. CONCLUSION: To conclude from the results of the present study, it can be said that FS, FF, FA, and CI are equally effective in treating IDA and they can be prescribed interchangeably.

Study of nuclear factor-2 erythroid related factor-2 activator, berberine, in paclitaxel induced peripheral neuropathy pain model in rats.

OBJECTIVES: The role of nuclear factor-2 erythroid related factor-2 (Nrf2) activator, berberine (BBR), has been established in rat model of streptozotocin induced diabetic neuropathy. Around 30-40% of cancer patients, on paclitaxel (PTX) chemotherapy develop peripheral neuropathy. The present study was contemplated with the aim of establishing the neuropathy preventive role of BBR, in paclitaxel induced peripheral neuropathy model in rats. METHODS: A total of 30 Wistar rats were divided into five groups as follows: Group I: dimethyl sulfoxide; Group II: PTX+ 0.9% NaCl; Group III: Amitriptyline (ATL) + PTX; Group IV: BBR (10 mg/kg) + PTX and Group V: BBR (20 mg/kg) + PTX. Animals were assessed for tail flick latency, tail cold allodynia latency, histopathological scores, oxidative stress parameters, and mRNA expression of the Nrf2 gene in the sciatic nerve. KEY FINDINGS: Berberine significantly increased the tail flick and tail cold allodynia latencies and significantly decreased the histopathological score. BBR reduced oxidative stress by significantly decreasing the lipid peroxidation, increasing the superoxide dismutase and reduced glutathione levels in the sciatic nerve. BBR also increased the mRNA expression of Nrf2 gene in rat sciatic nerve. CONCLUSIONS: All of these results showed the neuropathy preventing role of BBR in PTX induced neuropathy pain model in rats.

Inhalational supplementation of metformin butyrate: A strategy for prevention and cure of various pulmonary disorders.

The management of chronic lung diseases such as cancer, asthma, COPD and pulmonary hypertension remains unsatisfactory till date, and several strategies are being tried to control the same. Metformin, a popular anti-diabetic drug has shown promising effects in pre-clinical studies and has been subject to several trials in patients with debilitating pulmonary diseases. However, the clinical evidence for the use of metformin in these conditions is disappointing. Recent observations suggest that metformin use in diabetic patients is associated with an increase in butyrate-producing bacteria in the gut microbiome. Butyrate, similar to metformin, shows beneficial effects in pathological conditions found in pulmonary diseases. Further, the pharmacokinetic data of metformin suggests that metformin is predominantly concentrated in the gut, even after absorption. Butyrate, on the other hand, has a short half-life and thus oral supplementation of butyrate and metformin is unlikely to result in high concentrations of these drugs in the lung. In this paper, we review the pre-clinical studies of metformin and butyrate pertaining to pathologies commonly encountered in chronic lung diseases and underscore the need to administer these drugs directly to the lung via the inhalational route.

High dose targeted delivery on cancer sites and the importance of short-chain fatty acids for metformin's action: Two crucial aspects of the wonder drug.

Metformin is a popular anti-diabetic drug currently being explored for its role in cancer and gut microbiome amongst other areas. Recently, Adak T et al. explicatively reviewed metformin's effects as an anti-cancer drug and a gut microbiome modulator. We feel that the authors have not adequately addressed some of the key concerns around metformin in their report and in this correspondence, we seek to add some of the issues that need to be addressed by researchers.

A story of metformin-butyrate synergism to control various pathological conditions as a consequence of gut microbiome modification: Genesis of a wonder drug?

The most widely prescribed oral anti-diabetic agent today in the world today is a member of the biguanide class of drugs called metformin. Apart from its use in diabetes, it is currently being investigated for its potential use in many diseases such as cancer, cardiovascular diseases, Alzheimer's disease, obesity, comorbidities of diabetes such as retinopathy, nephropathy to name a few. Numerous in-vitro and in-vivo studies as well as clinical trials have been and are being conducted with a vast amount of literature being published every day. Numerous mechanisms for this drug have been proposed, but they have been unable to explain all the actions observed clinically. It is of interest that insulin has a stimulatory effect on cellular growth. Metformin sensitizes the insulin action but believed to be beneficial in cancer. Like -wise metformin is shown to have beneficial effects in opposite sets of pathological scenario looking from insulin sensitization point of view. This requires a comprehensive review of the disease conditions which are claimed to be affected by metformin therapy. Such a comprehensive review is presently lacking. In this review, we begin by examining the history of metformin before it became the most popular anti-diabetic medication today followed by a review of its relevant molecular mechanisms and important clinical trials in all areas where metformin has been studied and investigated till today. We also review novel mechanistic insight in metformin action in relation to microbiome and elaborate implications of such aspect in various disease states. Finally, we highlight the quandaries and suggest potential solutions which will help the researchers and physicians to channel their research and put this drug to better use.

Influence of pre-operative use of serotonergic antidepressants (SADs) on the risk of bleeding in patients undergoing different surgical interventions: a meta-analysis.

PURPOSE: Serotonergic antidepressants (SADs) are one of the most widely prescribed group of drugs. Of late, the use of SADs is being associated with an increased risk of perioperative bleeding. However, the results are inconsistent. The present analysis was planned to evaluate the association between preoperative SADs use and the risk of bleeding/mortality in patients undergoing surgery. METHODS: Studies that had reported the effects of preoperative SADs use on the perioperative bleeding outcomes and/or mortality in adult patients undergoing surgical interventions were identified and evaluated for inclusion in the analysis. Outcomes evaluated were reoperation for bleeding event, requirement of blood/RBC transfusion and mortality. A meta-analysis was conducted, and a pooled estimate of odds ratio (OR) was calculated using the inverse variance method. RESULTS: Eight cohort studies, comprising a total of 79 976 SADs users and 485 336 non-antidepressant users were included in the final analysis. SADs use was not associated with increased risk of requirement of reoperation for bleeding event [OR = 1.48 (0.84-2.62)]. However, there was an increased requirement of transfusion [OR = 1.19(1.09-1.30)], which was not observed in the subgroup of patients undergoing coronary artery bypass graft (CABG) [OR = 1.06(0.90-1.24)]. SADs use was associated with a substantial increase in mortality [OR = 1.53 (1.15-2.04)] in patients undergoing CABG but not in the overall population [OR = 1.1 (0.99-1.22)]. CONCLUSIONS: Preoperative SADs use is associated with increased bleeding risk with respect to requirement of transfusion; nevertheless, the results should not be generalized to all surgical groups. The divergence between bleeding risk and mortality in CABG surgery patients needs further evaluation.

Understanding the anti-kindling role and its mechanism of Resveratrol in Pentylenetetrazole induced-kindling in a rat model.

BACKGROUND: Resveratrol is a polyphone chemical found in a number of plant species, including peanuts and grapes, but with significant amounts in red wine. In normal plant physiology, Resveratrol is produced as a defensive response to injury or parasitic attacks. Resveratrol has diverse biological properties and actions with potential clinical applications, including anti-inflammatory, antioxidant, anti proliferative, and neuroprotective effects. AIM: The aim of the present study was to explore the effect and mechanism of Resveratrol in Pentylenetetrazole (PTZ) induced kindling in rats. MATERIALS AND METHODS: In a PTZ kindled Wistar rat model, different doses of Resveratrol (25mg/kg, 50mg/kg and 75 mg/kg) were administered orally 30 min before the PTZ injection. The PTZ injection was given on alternate day till the animal became fully kindled or till 10 weeks. The following parameters were compared between control and various experimental groups: the course of kindling, stages of seizures, histopathological scoring of hippocampus, antioxidant parameters, DNA fragmentation and caspase-3 expression in the hippocampus, and neuron-specific enolase in the blood. One way ANOVA followed by Bonferroni post hoc analysis and Fischer's Exact test were used for statistical analyses. THE RESULTS: In the present study, Resveratrol showed dose-dependent anti-seizure effect. Resveratrol (75 mg/kg) significantly increased the latency to myoclonic jerks, clinic seizures as well as generalized tonic-clinic seizures, improved the seizure score and decreased the number of myoclonic jerks. PTZ induced kindling caused a significant neuronal injury, oxidative stress and apoptosis which were reversed by pretreatment with Resveratrol in a dose-dependent manner. CONCLUSION: Our study suggests that Resveratrol has a potential antiepileptogenic effect on PTZ-induced kindling in rats. The possible underlying mechanisms of Resveratrol as an antiepileptic agent may be due to its antioxidative property and neuroprotective effect.

Comparative evaluation of different doses of PPAR-γ agonist alone and in combination with sulfasalazine in experimentally induced inflammatory bowel disease in rats.

BACKGROUND: Inflammatory bowel disease (IBD) is an idiopathic, chronic inflammatory condition, which affects the gastrointestinal tract and has no curative treatment. The present study aimed to investigate the effect of different doses of pioglitazone alone and in combination with sulfasalazine in TNBS (trinitrobenzenesulfonic acid)-induced inflammatory bowel disease (IBD) in rats. METHODS: A total of 36 animals were included in the study. Animals were divided into five groups (n = 6): group I--vehicle (ethanol), group II--TNBS + ethanol, group IIIA--TNBS + pioglitazone (15 mg/kg), group IIIB--TNBS + pioglitazone (30 mg/kg), group IV--TNBS + sulfasalazine (360 mg/kg), group V--TNBS + sulfasalazine (360 mg/kg) + pioglitazone (least effective dose found in group III). Group III was divided into two subgroups, namely IIIA and IIIB, on the basis of different doses of pioglitazone used. After completion of two weeks of treatment, rats were sacrificed under ether anesthesia by cervical dislocation for assessment of intestinal inflammation, histological analysis, myeloperoxidase assay, malondialdehyde assay and TNF-α estimation. RESULTS: All the drug-treated groups showed both gross morphological and microscopic score either 1 or 2. None of them showed score of > 2 on both gross and microscopic morphological examination. Both MDA levels and MPO activity were significantly reduced in the drug-treated groups, with maximum reduction seen in the combination group. TNF-α was reduced in pioglitazone group. It was highly reduced in sulfasalazine group (group V) as compared to TNBS group thereby indicating that pioglitazone is protective in TNBS-induced inflammatory bowel disease. CONCLUSION: The present study showed reduction in lipid peroxidation, malondialdehyde levels and TNF-α levels in pioglitazone-treated group and hence, there was significant improvement in gross and microscopic features, too. However, combination of pioglitazone and sulfasalazine has shown greater efficacy.

Preoperative statin therapy is associated with lower requirement of renal replacement therapy in patients undergoing cardiac surgery: a meta-analysis of observational studies.

OBJECTIVES: Acute kidney injury (AKI) following cardiac surgery is a common complication associated with serious morbidity and mortality. Activation of inflammatory cascade and vascular endothelial dysfunction plays a vital role during the perioperative period leading to AKI. Statins are known to suppress inflammation and improve endothelial dysfunction over and above the cholesterol lowering efficacy. METHODS: Observational studies with a defined population in terms of preoperative statin therapy and no preoperative statin therapy undergoing cardiac surgery (CABG, isolated valve surgery or both) and with reported data on the incidence of acute renal failure/injury and/or mortality were identified and analysed for inclusion in the analysis. Outcomes evaluated were occurrence of postoperative acute kidney injury/failure, requirement of any postoperative renal replacement therapy and short-term all-cause mortality rate. A meta-analysis was conducted and a pooled estimate of odds ratio (OR) was calculated using the inverse variance method. RESULTS: A total of 17 studies with a total population of 24 998 statin users and 22 082 non-statin users were included in the final analysis. PST resulted in a significantly lower incidence of renal replacement therapy in patients undergoing CABG (OR: 0.56 [0.41-0.76]) but not in isolated valve surgery (OR: 1.80 [0.73-4.44]). Also preoperative statin therapy resulted in a significantly lower postoperative mortality (0.72 [0.61-0.84]) irrespective of the type of surgery. There was no effect of preoperative statin therapy on the incidence of AKI in any of the sub-group of the patients. CONCLUSIONS: Patients undergoing CABG might derive benefit from preoperative statin therapy in terms of reducing the need for postoperative renal replacement therapy and mortality. However, the uncertainty concerning the reno-protective efficacy of preoperative statin therapy in patients undergoing isolated valve surgery needs further investigation.

Patterns of prescription drug use and incidence of drug-drug interactions in patients reporting to medical emergency.

Pharmaco-epidemiological studies detailing prescribing patterns of physicians are very few from developing countries. The present study describes the patterns of prescription of drugs by physicians working in different clinical settings in India and explores using the prescriptions the incidence of potential drug-drug interactions (DDI). This study was a cross-sectional observational study. The prescriptions of patients for any chronic medical condition and drug therapy received at the first point of contact with health care services for present medical emergency were analyzed for information. The prescriptions were also analyzed for potential DDI. Data were expressed as mean ± SD or median and inter-quartile range. Multiple logistic regression was used for variables likely to be associated with incidence of DDI. Of total 710 patients, 565 prescriptions were available for analysis. Of the chronic diseases, hypertension (17.7%) and diabetes mellitus (16.8%) were the commonest. Alcoholic liver disease had maximum average number of drugs prescribed (3.9). Supplements were the most commonly prescribed pharmacological agents for chronic disease (142/796). Patients in 35-50 years of age consumed maximum average number of drugs (1.9). Antibiotics were the most frequently prescribed agents (148/1240) followed by supplements (122/1240). We noted 296 mild and moderate potential DDI. Literacy of patients and polypharmacy were the factors associated significantly with DDI. Patients in India do not consume large number of allopathic medicines. The practice of prescribing supplements and antibiotics needs to be reviewed. Potential DDI are not an important problem. Prescription policies need significant revision.

Nicotine reversal of anticonvulsant action of topiramate in kainic acid-induced seizure model in mice.

INTRODUCTION: Tobacco smoking is a widespread phenomenon, and nicotine is the addictive component of tobacco. Nicotine acts through nicotinic cholinergic receptors and has been associated with different types of psychophysical disorders in human beings. The present study had explored the proconvulsive action of nicotine and its effect on the antiseizure efficacy of topiramate against kainic acid (KA)-induced seizures in mice. METHODS: The study had evaluated the dose-response curves for nicotine and KA and for KA in nicotine-pretreated mice and for topiramate against KA-induced seizures. Mecamylamine was used to antagonize the nicotinic receptor-mediated actions of nicotine. CD50 (convulsive dose in 50% of animals) for KA and nicotine and ED50 (effective dose in 50% of animals as anticonvulsant) for topiramate were determined. Brain lipid peroxidation studies were also undertaken in the treated mice. RESULTS: Nicotine significantly potentiated the convulsive action of KA acid and reduced the CD50 (95% confidence limits [CL]) value for KA from 2.6 mg/kg (2.3-3.1) to 1.4 mg/kg (0.9-2.1), intraperitoneally (i.p.). Topiramate pretreatment significantly inhibited KA-induced seizures and brain lipid peroxidation with ED50 (95% CL) value of 21.90 mg/kg (17.3-28.2), i.p. Nicotine pretreatment caused dose-dependent antagonism to the antiseizure and antilipid peroxidative actions of topiramate. Mecamylamine had antagonized the proconvulsant action of nicotine. CONCLUSION: The study highlights the fact that intake of nicotine, through agonism to nAChR, might predispose epileptic patients to lower seizure threshold and induce a state of refractoriness to the protective effects of the antiepileptic drugs, resulting in possible breakthrough seizure attacks.

Neuroprotective effect of pioglitazone on acute phase changes induced by partial global cerebral ischemia in mice.

Present study was carried out to investigate the possible neuroprotective effect of pioglitazone, an antidiabetic agent, peroxisome proliferator-activated receptor gamma (PPARgamma) agonist on acute phase changes in mice model of cerebral ischemia induced by Bilateral Common Carotid artery Occlusion (BCCAO). BCCAO model was used to induce partial global cerebral ischemia. BCCAO induced significant brain infarct size and edema in saline treated control group along with high increase in oxidative stress showed by increase lipid peroxidation and decreased levels of antioxidants like superoxide superoxide dismutage, catalase, glutathione peroxidase. Pioglitazone (20 mg/kg, orally) administration showed neuroprotective effects by reducing cerebral infarct size significantly as compared to control group. Postischemic seizure susceptibility was also reduced as number of positive responders decreased to a significant number. Brain edema was subsided to a significant level. Pioglitazone reduced the plasma TNF-alpha levels as compared to ischemia group significantly. Pioglitazone treatment also improved all the antioxidants levels showing activity against oxidative stress induced by BCCAO. Pioglitazone showed neuroprotection against ischemic insult suggesting the role of PPARgamma agonist in neuroprotective agents.

Intestinal inflammation and seizure susceptibility: understanding the role of tumour necrosis factor-alpha in a rat model.

OBJECTIVES: The aim of the study was to evaluate the correlation between colitis and susceptibility to seizures. METHODS: Colitis was induced in Wistar rats by a single intracolonic administration of trinitrobenzene sulfonic acid (TNBS; 20 mg in 35% ethanol). The control group were given intracolonic vehicle. One group of rats with colitis were treated with thalidomide (150 mg/kg p.o.) daily for 14 days. The other colitis group received vehicle only. On day 15, seizure susceptibility was tested by administration of pentylenetetrazole (40 mg/kg i.p.). Colonic tissue was collected for estimation of morphological score, and malondialdehyde, superoxide dismutase, catalase and glutathione peroxidase. Tumour necrosis factor (TNF)-alpha levels were measured in serum and brain samples. KEY FINDINGS: The colitis group showed a significant increase in seizure score and reduction in onset time compared with the control group. Thalidomide was protective against seizures, resulting in decreased seizure score and significantly delaying the onset of seizures. Thalidomide also provided significant protection against TNBS-induced colonic damage in terms of morphological and histological score and levels of lipid peroxidation, superoxide dismutase, catalase and glutathione peroxidase in colonic tissue. The level of TNF-alpha in serum was also reduced significantly whereas brain TNF-alpha level was reduced but not significantly. CONCLUSIONS: TNBS-induced colitis increased seizure susceptibility to a subconvulsive dose of pentylenetetrazole; the immunomodulator thalidomide was protective.

Dose-finding study with nicotine as a proconvulsant agent in PTZ-induced seizure model in mice.

The present study was conducted to investigate the possible interaction between low doses of nicotine and pentylenetetrazole (PTZ) in vivo and also to evaluate the influence of nicotine on the antiseizure efficacy of topiramate and sodium valproate in the PTZ-induced seizure model in mice. Graded dose-response study with nicotine showed the CD50 value for nicotine at 6.76 mg/kg. i.p. Subtheshold dose of nicotine (4 mg/kg, i.p.) pretreatment significantly decreased the CD50 value for PTZ from 47.86 mg/kg, i.p. (of PTZ per se) to 31.62 mg/kg, i.p. Sodium valproate but not topiramate, significantly inhibited PTZ-induced seizures in mice with an ED50 value of 177.83 mg/kg, i.p. Nonconvulsive dose of nicotine (1 mg/kg, i.p.) significantly antagonized the protective efficacy of sodium valproate against PTZ-induced seizures and increased the ED50 value to 338.84 mg/kg, i.p. PTZ-induced seizures significantly increased the mouse brain levels of MDA and reduced the level of GSH while sodium valproate reversed such changes. Nicotine pretreatment reversed the anti-lipid peroxidative action of sodium valproate in the PTZ-induced seizure model in mice. The study highlighted the convulsant as well as proconvulsant role of nicotine and established dose discrimination for nicotine as a proconvulsant agent and an anti-antiseizure agent. The study bears significant clinical relevance particularly amongst epileptic smokers who may show failure of efficacy of antiepileptic agents and present with breakthrough seizure attacks on exposure to nicotine.

Neuroprotective effect of progesterone on acute phase changes induced by partial global cerebral ischaemia in mice.

The possible neuroprotective effect of progesterone, a steroid hormone, on acute phase changes in a mouse model of cerebral ischaemia induced by bilateral common carotid artery occlusion (BCAO) was studied. A total of 72 male mice were included in the study. The BCAO model was used to induce partial global cerebral ischaemia. Morphological assessment included measurement of infarct size and brain oedema. Post-ischaemic seizure susceptibility was assessed using a subconvulsive dose of pentylenetetrazole (30 mgkg(-1) i.p.). Biochemical estimations included tumour necrosis factor alpha (TNF-alpha) levels and enzyme parameters such as lipid peroxidation, superoxide dismutase, catalase and glutathione peroxidase, and protein estimation. BCAO induced a significant infarct size and oedema in the saline-treated control group, along with an increase in oxidative stress, indicated by increased lipid peroxidation and decreased levels of antioxidants such as superoxide dismutase, catalase and glutathione peroxidase. Progesterone (15 mgkg(-1) i.p.) administration showed a neuro-protective effect by significantly reducing the cerebral infarct size as compared with the control group. Post-ischaemic seizure susceptibility was also reduced as the number of positive responders decreased. Brain oedema subsided, but not significantly. Progesterone significantly reduced TNF-alpha levels compared with the ischaemia group. Progesterone improved levels of all the antioxidants, indicating activity against oxidative stress induced by BCAO. The results demonstrate the neuroprotective effect of progesterone against ischaemic insult, suggesting a role for the steroid as a neuroprotective agent.