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.

Neuroprotective effect of Berberine Nanoparticles Against Seizures in Pentylenetetrazole Induced Kindling Model of Epileptogenesis: Role of Anti-Oxidative, Anti-Inflammatory, and Anti-Apoptotic Mechanisms.

There is an unmet need to develop alternative therapeutic strategies to not only restrain seizures but also to alleviate the underlying pathologies and sequelae. Berberine (BBR), an isoquinoline alkaloid, has shown promising effect in the kindling model of epileptogenesis, but due to the poor oral bioavailability its clinical application is limited. So, the present study was designed to study the neuroprotective effect of BBR nanoparticles (enhanced bioavailability as compared to BBR) against seizures in pentylenetetrazole (PTZ) induced kindling model of epileptogenesis. Kindling model was established in male Wistar rats by intraperitoneal (i.p.) administration of PTZ (30 mg/kg) on every alternate day till the animal became fully kindled or till 6 weeks. Three doses of BBR (50, 100, and 200 mg/kg) and nano-BBR (25, 50, 100 mg/kg) were studied for seizure score, percentage of animal kindled, histopathological score, oxidative stress, inflammation, and apoptosis in PTZ treated rats by conducting cytokines, gene expression and protein expression analysis. BBR nanoparticles showed significant effect on the seizure score and percentage of animal kindled, histopathological score, neurobehavioral parameters (Forced swim test, Rotarod), oxidative (MDA, SOD, GSH, GPx) and inflammatory (IL-1beta, TNF-alpha) parameters, apoptotic parameters (Bax and iNOS), and gene (Nrf2, NQO1, HO1) and protein expression (Nrf2) as compared to both PTZ and BBR. BBR nanoparticles showed neuroprotective effect in PTZ induced kindling model of epileptogenesis and proves to be a promising antiepileptogenic therapy for the patients who are at high risk of developing seizures.

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.

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.

Antiapoptotic and neuroprotective role of Curcumin in Pentylenetetrazole (PTZ) induced kindling model in rat.

Kindling, a sub threshold chemical or electrical stimulation, increases seizure duration and enhances accompanied behavior until it reaches a sort of equilibrium state. The present study aimed to explore the effect of curcumin on the development of kindling in PTZ kindled rats and its role in apoptosis and neuronal damage. In a PTZ kindled Wistar rat model, different doses of curcumin (100, 200 and 300 mg/kg) were administrated orally one hour before the PTZ injections on alternate day during the whole kindling days. The following parameters were compared between control and experimental groups: the course of kindling, stages of seizures, Histopathological scoring of hippocampus, antioxidant parameters in the hippocampus, DNA fragmentation and caspase-3 expression in 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. PTZ, 30 mg/kg, induced kindling in rats after 32.0 ± 1.4 days. Curcumin showed dose-dependent anti-seizure effect. Curcumin (300 mg/kg) significantly increased the latency to myoclonic jerks, clonic seizures as well as generalized tonic-clonic seizures, improved the seizure score and decreased the number of myoclonic jerks. PTZ kindling induced a significant neuronal injury, oxidative stress and apoptosis which were reversed by pretreatment with curcumin in a dose-dependent manner. Our study suggests that curcumin has a potential antiepileptogenic effect on kindling-induced epileptogenesis.

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.

Pentylenetetrazole Induced Kindling Model of Refractory Epilepsy: A Proof-of-concept Study to Explore Dose and Time Range of Phenobarbital in Rats.

Introduction: Drug-resistant epilepsy is an unmet medical condition that impacts 30% of epileptic patients. Numerous antiseizure drugs have already been developed but they provide only symptomatic relief and do not target the underlying pathogenesis. Preclinical models provide opportunities to gain insights into obscure mechanisms of drug-resistant epilepsy. Current animal models possess lacunae that need rectification and validation to discover novel antiepileptic drugs. The present study aims to validate 3 different doses of phenobarbital at 2 different periods. Methods: Pentylenetetrazole was given at a sub-convulsive dose (30 mg/kg/day/intraperitoneal [IP]) for 28 days to develop kindling in male Wistar rats. Further, kindled rats were divided into the following four groups: Pentylenetetrazole control, pentylenetetrazole and phenobarbital (20 mg/kg), pentylenetetrazole and phenobarbital 40 mg/kg, and pentylenetetrazole and phenobarbital (60 mg/kg). They were assessed on days 14 and 28 post-kindling. Seizure scoring, oxidative stress, phenobarbital plasma levels, and histopathology of hippocampal neurons were analyzed. Results: The results showed that the combination of pentylenetetrazole and phenobarbital (40 and 60 mg/kg) remarkably decreased seizure score, elucidated higher antioxidant effect, and prevented neuronal injury on day 14, whereas increased seizure score, oxidative stress, and neuronal death was observed with chronic administration of pentylenetetrazole and phenobarbital in kindled rats at day 28. Moreover, phenobarbital levels in blood were significantly increased at day 28 of phenobarbital treatment compared to day 14. Conclusion: The adapted protocol with phenobarbital 40 mg/kg dose could be of great potential in screening antiseizure drugs in refractory epilepsy.

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.

Neuroprotective Effect of Celastrus Paniculatus Seed Extract on Epilepsy and Epilepsy-associated Cognitive Deficits.

Introduction: Cognitive deficit is one of the common comorbidity accompanying epilepsy. The present study evaluated the effect of Celastrus paniculatus seed extract on seizure severity and cognitive deficit following the pentylenetetrazole (PTZ)-induced chemical kindling model. Methods: PTZ kindling model was developed by daily administration of the sub-convulsive dose of PTZ 30 mg/kg for four weeks. After four weeks of induction, the following treatment, namely sodium valproic acid (SVA) 200 mg/kg, C. paniculatus 500 mg\kg, pergolide 2 mg/kg, C. paniculatus (250 mg\kg)+ Pergolide (1 mg/kg), and C. paniculatus (250 mg\kg)+ SVA (100 mg/kg) were administered 30 minutes prior to PTZ (30 mg/kg) injection for a period of next 14 days. Neurobehavioral parameters, including superoxide dismutase (SOD), Catalase (CAT), glutathione (GSH), and dopamine levels were assessed and the Morris water maze test (MWM) and Grip strength test (GPS) were performed. Hematoxylin & Eosin (H&E) staining of hippocampal cornu ammonis (CA1), CA2, CA3, dentate gyrus (DG), and frontal cortex was performed. Results: C. paniculatus (500 mg/kg) alone and in combination (C. paniculatus (250 mg\ kg)+ pergolide (1 mg/kg) and C. paniculatus (250 mg\kg)+ SVA (100 mg/kg)) significantly (P<0.05) reduced the seizure score, mean latency time, and distance traveled in the MWM. However, no significant effect was seen in GPS. Biochemical analysis showed elevated antioxidant markers, namely GSH, CAT, and SOD, and also elevated dopamine levels. C. paniculatus and its combination also significantly (P<0.05) protected against neuronal loss in the hippocampus and frontal cortex evidenced by H&E staining. Conclusion: C. paniculatus alone and in combination with other agents may have the potential to treat epilepsy and associated cognitive deficits.

Study of fingolimod, nitric oxide inhibitor, and P-glycoprotein inhibitor in modulating the P-glycoprotein expression via an endothelin-sphingolipid pathway in an animal model of pharmacoresistant epilepsy.

BACKGROUND: The overexpression of P-glycoprotein (P-gp) contributes to drug resistance in patients with epilepsy, and the change of P-gp expression located at the blood-brain barrier alienates the anti-seizure effects of P-gp substrates. Thus, the present study explored the effect of fingolimod (FTY720) acting through an endothelin-sphingolipid pathway on P-gp-induced pentylenetetrazol (PTZ)-kindled phenobarbital (PB)-resistant rats. MATERIALS AND METHODS: PTZ kindling (30 mg/kg; i.p.) and PB (40 mg/kg; orally) were used to develop an animal model of refractory epilepsy. The effect of Fingolimod on seizure score (Racine scale), plasma and brain levels of PB (high-performance liquid chromatography), and blood-brain barrier permeability (Evans blue dye) was determined. Further, Fingolimod's neuroprotective effect was determined by measuring the levels of various inflammatory cytokines, oxidative stress parameters, and neurotrophic factors in rat brain homogenate. The Fingolimod's effect on P-gp expression was estimated by reverse transcriptase-polymerase chain reaction and immunohistochemistry in rat brain. The H and E staining was done to determine the neuronal injury. RESULTS: Fingolimod significantly (P < 0.001) reduced the seizure score in a dose-dependent manner and alleviated the blood-brain barrier permeability. It decreased the P-gp expression, which further increased the brain PB concentration. Fingolimod significantly (P < 0.01) reduced oxidative stress as well as inflammation. Moreover, it attenuated the raised neuronal injury score in a resistant model of epilepsy. CONCLUSION: The modulation of the P-gp expression by Fingolimod improved drug delivery to the brain in an animal model of refractory epilepsy. Therefore, S1P signaling could serve as an additional therapeutic target to overcome refractoriness.

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.

Evaluation of effect of isoflavone on thyroid economy & autoimmunity in oophorectomised women: a randomised, double-blind, placebo-controlled trial.

BACKGROUND AND OBJECTIVES: The potential of soy isoflavones to interfere with thyroid function has been reported. However, there are limited data regarding their effect on thyroid function and autoimmunity in surgical menopausal women. The present study aimed to evaluate the effect of isoflavones on thyroid function and autoimmunity, menopausal symptoms, serum follicle stimulating hormone (FSH) and estradiol levels in oophorectomised women. METHODS: A randomized, double blind, placebo-controlled trial was conducted in 43 oophorectomised women to evaluate the effect of soy isoflavones (75 mg/day for 12 wk) on serum thyroid profile (free T3, free T4, TSH, TBG and anti-TPO antibody titres) assessed at baseline, 6 and 12 wk after randomization. Assessment was also done for menopause symptom score (MSS) three weekly, and FSH and estradiol levels at baseline and at study completion. RESULTS: There was a significant alteration in free T3 levels in the group receiving isoflavones (4.05 ± 0.36, 4.12 ± 0.69 and 3.76 ± 0.55 pmol/l at baseline, 6 and 12 wk, respectively; P=0.02). However, the mean change in various thyroid parameters at 12 wk from baseline was not significantly different between the two groups. MSS was also significantly decreased at 9 and 12 wk from baseline with isoflavones (12.47 ± 8.15, 9.35 ± 5.23 and 9 ± 5.14 at baseline, 9 and 12 wk respectively; P=0.004) with significant improvement in urogenital symptoms compared to placebo. Isoflavones did not significantly affect other parameters during study period. There were no serious adverse events reported and the proportion of patients experiencing adverse events was similar between the two groups. INTERPRETATION AND CONCLUSIONS: Modest reduction in serum free T3 levels in the isoflavone group in the absence of any effect on other thyroid parameters might be considered clinically unimportant.

Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy: A randomized, double-blind, active-control, crossover clinical trial.

BACKGROUND: There is a need for newer therapies for chronic painful diabetic neuropathy as the existing drugs have their own limitations. Clinical trials on low-dose naltrexone (1-5 mg/d) showed efficacy and safety in certain chronic painful conditions, but not in painful diabetic neuropathy. Hence the present study was planned. METHODS: Sixty-seven participants with painful diabetic neuropathy were randomized to receive either 2 mg naltrexone or 10 mg amitriptyline daily following a 2-week run-in period. The participants were followed up every 2 weeks for a total of 6 weeks. Up-titration was done (to 4 mg naltrexone or 25/50 mg amitriptyline) if the pain reduction was less than 20% on the visual analog scale (VAS) during the next follow-up visit. Efficacy was assessed using the change in VAS score at the end of 6 weeks from baseline. Safety was evaluated at each follow-up visit. After 2 weeks of washout period, the participants were crossed over to receive the comparator drug for another 6 weeks with similar evaluations. RESULTS: The difference (confidence interval) in the change in VAS score between groups from baseline was 1.64 (-0.92 to 4.20) in per-protocol analysis and 1.5 (-1.11 to 4.13) in intention-to-treat analysis. Eight and fifty-two adverse events were reported in the naltrexone and amitriptyline groups, respectively (P < .001). The most common adverse events were mild diarrhea with naltrexone and somnolence with amitriptyline. CONCLUSIONS: Low-dose naltrexone exhibited similar efficacy and a superior safety profile compared with amitriptyline in painful diabetic neuropathy.

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.

Evaluation of antihyperalgesic effect of curcumin on formalin-induced orofacial pain in rat.

The present study was planned to evaluate the role of curcumin in the formalin-induced orofacial pain in rats that mimics typical human orofacial pain. Adult Wistar rats of either sex received an injection of 50 microL of 5% v/v subcutaneous formalin injection into one vibrissal pad and consequent facial grooming behavior was monitored. Animals exhibited two distinct periods of nocifensive grooming: (a) an acute phase lasting 0-6 min; and (b) a tonic phase lasting 6-45 min. The analgesic response of curcumin was observed at doses of 25, 50, 100, 200, 400 and 600 mg/kg i.p., administered 15 min prior to formalin injection. Another group received subanalgesic dose of diclofenac (0.2 mg/kg) and curcumin 25 mg/kg. Curcumin and diclofenac were administered 15 and 5 min prior to formalin injection respectively. Curcumin produced a dose-dependent inhibition of facial grooming in both acute and tonic phases compared to vehicle and potentiated the subanalgesic dose of diclofenac. The study results for the first time demonstrated the per se antinocifensive effect of curcumin and also exhibited a synergistic interaction with the subanalgesic dose of an NSAID in the facial pain model. More studies are necessary to elucidate the mechanisms of curcumin in this model of pain.

Effect of dimethyl fumarate on neuroinflammation and apoptosis in pentylenetetrazol kindling model in rats.

OBJECTIVE: Role of apoptosis and neuroinflammation have been well established in the pathogenesis of epilepsy. It has been reported that the activation of nuclear factor-erythroid 2-related factor-2 (Nrf2) contributes to the attenuation of inflammation by inhibiting nuclear factor-kB (NF-kB) pathway. Therefore, the present study was designed to evaluate anti-inflammatory and anti-apoptotic role of dimethyl fumarate (DMF), an activator of Nrf2, in chemical kindling model in rats. METHODS: Chemical kindling model was established in Wistar rats by intraperitoneal (i.p.) administration of pentylenetetrazole (PTZ). Animals were treated with DMF (60 mg/kg) to activate the Nrf2 antioxidant response element (ARE) pathway. The animals were assessed for seizure score, neuronal damage and inflammatory cytokines levels (IL-1ß, IL-6 and TNF-α) in hippocampus. The mRNA levels of various genes (Nrf2, HO-1, NQO1, Bcl2, Bax, Caspase 3, NF-kB, IL-6, IL-1ß and TNF-α) were quantified by real-time PCR. The expression of anti-oxidative (Nrf2), apoptotic (Bax, Bcl2) and inflammatory (NF-kB) proteins were analysed by western blot. Immunohistochemistry (Bax) and electron microscopy were done to assess apoptosis. RESULTS: The results showed reduction in the seizure score, percentage of kindled rats and neurological damage score in DMF treated rats. Pro-inflammatory cytokines concentrations were also decreased by DMF treatment. DMF downregulated the expression of inflammatory (NF-kB) and apoptotic (Bax, Caspase-3) genes and protein. DMF treatment increased the gene expression of Nrf2, HO-1, NQO1, Bcl-2 and protein expression of Nrf2 and Bcl2. CONCLUSION: DMF demonstrated anti-apoptotic, anti-inflammatory and anti-oxidative effect in hippocampus, which might be regulated by increased level of antioxidant response elements.

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.

A New Therapeutic Approach for Brain Delivery of Epigallocatechin Gallate: Development and Characterization Studies.

BACKGROUND: Blood-brain permeability is the primary concern when dealing with the biodistribution of drugs to the brain in neurological diseases. OBJECTIVE: The purpose of the study is to develop the nanoformulation of Epigallocatechin gallate (EGCG) in order to improve its bioavailability and penetration into the brain. METHODS: EGCG loaded Solid Lipid Nanoparticles (SLNs) have been developed using microemulsification method and pharmacological assessments were performed. RESULTS: Surface morphology and micromeritics analysis showed the successful development of EGCG loaded solid lipid nanoparticles with an average size of 162.4 nm and spherical in shape. In vitro release studies indicated a consistent and slow drug release. Pharmacological evaluation of SLN-EGCG demonstrated a significant improvement in cerebral ischemia-induced memory impairment. CONCLUSION: The results indicate that the EGCG loaded SLNs provide a potential drug delivery system for improved delivery of EGCG to the brain, hence, enhancing its brain bioavailability.