Damanpreet Singh

Synergistic effect of curcumin and piperine in suppression of DENA-induced hepatocellular carcinoma in rats

Curcumin has been reported to suppress different types of clinical and experimentally-induced tumors, but due to less absorption and quick metabolism it show poor bioavailability. The present study was envisaged to investigate the possible synergistic effect of combined treatment of curcumin with piperine in suppression of diethylnitrosamine (DENA)-induced hepatocellular carcinoma (HCC) in rats, owing to permeability enhancing effect of latter. HCC was induced by supplying DENA (0.01%) in drinking water for 10 weeks. The rats were treated with curcumin (100mg/kg; p.o.) per se and curcumin along with piperine (20mg/kg; p.o.) for 4 weeks post HCC induction. The combined treatment significantly attenuated the morphological, histopathological, biochemical, apoptotic and proliferative changes in the liver and serum in comparison to curcumin per se and vehicle control group. The results of present study concluded that curcumin in combination with piperine shows better suppression of DENA-induced HCC in contrast to curcumin per se.

Crocin Attenuates Kindling Development and Associated Cognitive Impairments in Mice via Inhibiting Reactive Oxygen Species-Mediated NF-κB Activation

Crocin is a pharmacologically active carotenoid pigment mainly present in the stigmas of Crocus sativus L. (Iridaceae). It has been well explored in experimental animal models of cognitive impairments, depression, anxiety and epilepsy. This study was designed to understand the effect of crocin on pentylenetetrazol (PTZ)‐induced kindling development and its associated cognitive deficit in mouse. Crocin treatment at 5, 10 and 20 mg/kg p.o. doses showed a marked reduction in severity of PTZ‐induced seizures. There was an increase in novel object preference index and discrimination ratio in the crocin‐treated groups in the novel object recognition test. Its treatment also increased percentage spontaneous alternations in T‐maze test at all the tested doses. Histopathological examination by Nissl staining showed a reduction in dark neurons in the hippocampal pyramidal layer of crocin‐treated animals in contrast to vehicle control, indicating a decrease in neuronal damage. Biochemical estimations showed a significant increase in superoxide dismutase activity and reduced reactive oxygen species (ROS) in the hippocampus of crocin‐treated animals. Immunohistochemistry results revealed attenuation in the levels of nuclear factor‐κB (NF‐κB) and phosphorylated NF‐κB in the hippocampal sections of crocin‐treated animals. The results of this study concluded that crocin treatment increased seizure threshold, thus inhibiting PTZ‐induced kindling development and improving cognitive functions. The effect was found to be due to suppression of seizure‐induced ROS generation and its linked NF‐κB pathway‐associated neuronal damage.

Anticancer Mammalian Target of Rapamycin (mTOR) Signaling Pathway Inhibitors: Current Status, Challenges and Future Prospects in Management of Epilepsy

The role of phosphatidylinositol 3-kinase linked mammalian target of rapamycin (mTOR) pathway hyperactivation is well established in cancer pathogenesis. Several molecules inhibiting mTOR pathway, leading to inhibition of protein synthesis responsible for angiogenesis of tumor cells have emerged out to be potential anticancers. Similar hyperactivation of mTOR pathway has also reported in epilepsy during latent phase, following precipitating injury causing reorganization of neuronal networks and ultimately leading to induction of seizures. The mTOR inhibitors have also found to attenuate pathological changes in the brain associated with epilepsy, primarily suppression of mossy fiber sprouting. At the same time, a few antiepileptic molecules which have been studied against cancer showed anticancer activity, apart from their principal mechanism of action. These studies suggest mTOR signaling pathway to be a common pathogenic link between cancer and epilepsy. It has been found that, anticancer molecules acting on different molecular targets, that ultimately down regulate the expression of mTOR, can also be used in case of epilepsy to reduce its hyperactivation. There are several unexplored anticancer molecules that act by inhibiting mTOR directly or indirectly available which can be explored as antiepileptic in future. Majority of the molecules which are tested as anticancer do not reach the final phases of clinical trials due to less potency and efficacy, and ultimately a few of them reach the market. Since a lot of experimental/safety studies have already been conducted on such molecules, hence it is worthwhile to test these molecules for other disorders that share common pathogenic pathway like epilepsy, provided their pitfalls have been addressed, as proposed in the present review.

Ginkgo biloba L. attenuates spontaneous recurrent seizures and associated neurological conditions in lithium-pilocarpine rat model of temporal lobe epilepsy through inhibition of mammalian target of rapamycin pathway hyperactivation

ETHNOPHARMACOLOGICAL RELEVANCE Ginkgo biloba L. (Ginkgoaceae) has been widely used in traditional medicine for variety of neurological conditions particularly behavioral and memory impairments. AIM OF THE STUDY The present study was envisaged to explore the effect of a standardized fraction of Ginkgo biloba leaves (GBbf) in rat model of lithium-pilocarpine induced spontaneous recurrent seizures, and associated behavioral impairments and cognitive deficit. MATERIALS AND METHODS Rats showing appearance of spontaneous recurrent seizures following lithium pilocarpine (LiPc)-induced status epilepticus (SE) were treated with different doses of GBbf or vehicle for subsequent 4 weeks. The severity of seizures and aggression in rats were scored following treatment with GBbf. Further, open field, forced swim, novel object recognition and Morris water maze tests were conducted. Histopathological, protein levels and gene expression studies were performed in the isolated brains. RESULTS Treatment with GBbf reduced seizure severity score and aggression in epileptic animals. Improved spatial cognitive functions and recognition memory, along with reduction in anxiety-like behavior were also observed in the treated animals. Histopathological examination by Nissl staining showed reduction in neuronal damage in the hippocampal pyramidal layer. The dentate gyrus and Cornu Ammonis 3 regions of the hippocampus showed reduction in mossy fiber sprouting. GBbf treatment attenuated ribosomal S6 and pS6 proteins, and hippocampal mTOR, Rps6 and Rps6kb1 mRNA levels. CONCLUSIONS The results of present study concluded that GBbf treatment suppressed lithium-pilocarpine induced spontaneous recurrent seizures severity and incidence with improved cognitive functions, reduced anxiety-like behavior and aggression. The effect was found to be due to inhibition of mTOR pathway hyperactivation linked with recurrent seizures.

Iridoid glycosides fraction from Picrorhiza kurroa attenuates cyclophosphamide-induced renal toxicity and peripheral neuropathy via PPAR-γ mediated inhibition of inflammation and apoptosis

BACKGROUND Picrorhiza kurroa Royle (Scrophulariaceae) is an important medicinal herb being widely used in variety of ailments. PURPOSE The present study was envisaged to evaluate the effects of iridoid glycosides enriched fraction (IGs) from Picrorhiza kurroa rhizome against cyclophosphamide (CP) -induced renal toxicity and peripheral neuropathy. METHODS Mice in different groups were pretreated with 25, 50 and 100 mg/kg; p.o. doses of IGs for 21 days, followed by cyclophosphamide intoxication for consecutive two days. Further, to identify the putative role of PPAR-γ receptors for the protective effect of IGs, an additional group of mice were pretreated with PPAR-γ antagonist BADGE (5 mg/kg; i.p.) followed by IGs (100 mg/kg; p.o.) for 21 days before CP intoxication. RESULTS IGs pretreatment decreased the hyperalgesic responses toward acetone and heat in acetone drop and tail immersion tests. The abolition of intramyelin odema, cytoplasmic vacuolization and axonal degeneration of sciatic nerve were observed in IGs pretreated mice in a dose-dependent manner. IGs treatment also attenuated the altered serum biochemical markers for renal injury. Furthermore, the treatment prevented renal tubular swelling, granular degeneration and glomerular damage. The levels of IL-1β and TNFα in different group revealed the anti-inflammatory effect of IGs, which was further confirmed by improvement in altered expressions of NF-kB in kidney and sciatic serve. Bax/Bcl-2 expressions and caspase 3/9 activity in renal tissues showed the anti-apoptotic effect of IGs. IGs pretreatment also improved the PPAR-γ expression in the kidney tissues. All the observed protective effects of IGs were suppressed after pretreatment with BADGE. CONCLUSION Present study concludes that IGs from Picrorhiza kurroa attenuates CP-induced renal toxicity and peripheral neuropathy via PPAR-γ -mediated pathways.

Targeting glycogen synthase kinase-3 for oxidative stress and neuroinflammation: Opportunities, challenges and future directions for cerebral stroke management

ABSTRACT Cerebral stroke is a leading cause of early death and physical disability in adults throughout the world. Oxidative stress and inflammation plays an important role in the pathological process associated with the stroke. The available reperfusion therapy itself enhances the oxidative stress by overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) from the neurons, as well as non‐neuronal cells, thus further worsens the condition. Excessive ROS and RNS production contributes to the brain injury during or after the stroke by activating inflammatory processes. Glycogen synthase kinase‐3 (Gsk‐3) is an evolutionary conserved serine‐threonine kinase that plays an important role in cellular growth, development, inflammation and apoptosis processes. Gsk‐3 is activated during the brain stroke and suppresses the expression of nuclear factor‐E2‐related factor 2, an important regulator of endogenous antioxidant defence mechanism. It also modulates the expression of anti‐inflammatory protein like, cAMP response element binding protein and activator protein 1. It has been found that the inhibition of Gsk‐3 shows neuroprotection via reducing the oxidative stress and inflammation in cerebral ischemia/reperfusion. The present review describes in depth the role of oxidative stress, neuroinflammatory processes and endogenous defence systems involved in cerebral stroke pathogenesis, and their regulation by Gsk‐3. Further the reports of all the potential agents modulating Gsk‐3 activity via different signalling pathways have been summarized to substantiate its effectiveness in cerebral stroke management. HIGHLIGHTSGsk‐3 plays an integral role in cerebral stroke pathogenesis.Oxidative stress during ischemia modulates the Gsk‐3 activity.Nrf2 expression is altered following Gsk‐3 activation.Activated Gsk‐3 enhances neuro inflammatory processes.Gsk‐3 inhibition can be a potential therapy for management of cerebral stroke.

Mycophenolate mofetil contributes to downregulation of the hippocampal interleukin type 2 and 1β mediated PI3K/AKT/mTOR pathway hyperactivation and attenuates neurobehavioral comorbidities in a rat model of temporal lobe epilepsy

The role of neuroinflammatory mediators has been well established in the pathogenesis of temporal lobe epilepsy (TLE) and associated neurobehavioral comorbidities. Mycophenolate mofetil (MMF) is commonly used as an immunosuppressant in organ transplantations. Its neuroprotective effect is well explored in different preclinical and clinical studies. The present study was designed to investigate the effect of MMF in rat model of lithium pilocarpine (LiPc)-induced spontaneous recurrent seizures and its associated neurobehavioral comorbidities. MMF treatment showed a dose-dependent decrease in seizure severity and reduced aggression in epileptic rats. There was marked improvement in spatial and recognition memory functions, along with substantial decrease in depression-like behavior in MMF treated epileptic rats. There was considerable decrease in mossy fiber sprouting in the dentate gyrus and the cornu ammonis 3 regions of the hippocampus, along with reduction in neuronal death in the treated groups. Furthermore, the hippocampal mRNA level of IL-1β, IL-2, PI3K, AKT, HIF-1α, RAPTOR, mTOR, Rps6kb1 and Rps6 was found to be decreased in MMF treated animals. mTOR, S6, pS6 and GFAP protein expression was decreased, whereas NeuN was increased in the rat hippocampus of the treated animals. The results concluded that MMF suppress recurrent seizures, and improves its associated behavioral impairments and cognitive deficit in rat model of TLE. The observed effects of MMF be correlated with the inhibition of IL-2 and IL-1β linked PI3K/AKT/mTOR signaling pathway hyperactivation.

Radiological profile of neurocysticercosis in children in North India

Neurocysticercosis is the most common parasitic disease of the human nervous system. Its prevalence varies greatly according to the geographical region and is not yet precisely known. 1 Neurocysticercosis caused by Taenia solium, is a leading cause of Acquired epilepsy worldwide. 2 Neurocysticercosis predominantly affects adults in their third or fourth decade of life; it is uncommon in children and elderly people. 3 Reports of cysticercosis are very unlikely in children younger than 2 years because the incubation period of T. solium is long. The disease is recognized mainly in children older than 7 years, owing to this incubation period. Clinical presentation of NCC varies from an asymptomatic infection to sudden death. Differences in the clinical picture depend on the number, size, stage and localization of cysts and the patient’s immune response. Seizures are the commonest Presentation of NCC (5080%). 4 Various types of seizures have been described among patients with NCC including generalized, focal and rarely myoclonus and acquired epileptic aphasia. In general, it seems that about half the cases have partial seizures and the other half generalized seizures, a proportion similar to that of the general population. 5