Dietary flavonoids-rich Citrus reticulata peel extract interacts with CREB signaling to suppress seizures and linked neurobehavioral impairments in a kindling mouse model.

Objectives: The citrus fruits peel contains a variety of bioactive metabolites that have shown multiple therapeutic effects. However, despite having substantial ethnomedicinal value, citrus peels remained underexplored and regarded as bio-waste. This present study was planned to investigate the effect of a characterized peel extract of Citrus reticulata c.v. (CRE) in pentylenetetrazole (PTZ)-induced kindling and associated cognitive and behavioral impairments in a mouse model.Methods: The kindled animals were treated daily with CRE (100 and 200 mg/kg) and challenged with a sub-effective dose of PTZ every 5th day to record the severity of seizures. In the end, different tests were performed to record behavioral and cognitive performance.Results: CRE-treated kindled animals showed a significant suppression in seizure severity following 20 days of the treatment. In the T-maze test, the extract treatment resulted in a marked increase in the spontaneous alternations, whereas it showed no change in anxiety behavior of kindled animals in the elevated plus-maze test. In both forced swim and tail suspension tests, CRE treatment demonstrated a considerable reduction in immobility time. However, no change in overall locomotion was observed in the open field test among all the groups. An increase in the hippocampal Creb and Bdnf expression and decreased glutamate-to-GABA ratio were observed in the CRE-treated kindled animals.Discussion: The results showed that CRE treatment suppresses epileptic seizures and associated cognitive deficits and depression-like behavior in kindled mice. The gene expression findings supported that the observed protective effects of CRE be due to its interaction with CREB signaling.

Buckwheat tartary regulates the Gsk-3ß/ß-catenin pathway to prevent neurobehavioral impairments in a rat model of surgical menopause.

Menopause is a natural aging process characterized by decreased levels of sex hormones in females. Deprivation of estrogen following menopause results in alterations of dendritic arborization of the neuron that leads to neurobehavioral complications. Hormone replacement therapy is in practice to manage postmenopausal conditions but is associated with a lot of adverse effects. In the present study, the efficacy of buckwheat tartary (Fagopyrum tataricum) whole seed extract was investigated against the neurobehavioral complication in middle-aged ovariectomized rats, which mimic the clinical postmenopausal condition. Hydroalcoholic extraction (80% ethanol) was done, and quantification of major marker compounds in the extract was performed using HPLC. Oral treatment of the extract following the critical window period rescued the reconsolidation process of spatial and recognition memory, as well as depression-like behavior. Gene expression analysis disclosed elevated oxidative stress and neuroinflammation that largely disturb the integrity of the blood-brain barrier in ovariectomized rats. Gfap and Pparγ expression also showed reactive astrogliosis in the rats subjected to ovariectomy. The extract treatment reverted the elevated oxidative stress, neuroinflammation and expression of the studied genes. Furthermore, protein expression analysis revealed that Gsk-3ß was activated differentially in the brain, as suggested by ß-catenin protein expression, which was normalized following the treatment with extract and rescued the altered neurobehavioral process. The results of the current study concluded that Fagopyrum tataricum seed extract is better option to overcome the neurobehavioral complications associated with the menopause.

Deciphering key regulators involved in epilepsy-induced cardiac damage through whole transcriptome and proteome analysis in a rat model.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is a major outcome of cardiac dysfunction in patients with epilepsy. In continuation of our previous work, the present study was envisaged to explore the key regulators responsible for cardiac damage associated with chronic seizures using whole transcriptome and proteome analysis in a rat model of temporal lobe epilepsy. METHODS: A standard lithium-pilocarpine protocol was used to induce recurrent seizures in rats. The isolated rat heart tissue was subjected to transcriptomic and proteomic analysis. An integrated approach of RNA-Seq, proteomics, and system biology analysis was used to identify key regulators involved in seizure-linked cardiac changes. The analyzed differential expression patterns and network interactions were supported by gene and protein expression studies. RESULTS: Altogether, 1157 differentially expressed genes and 1264 proteins were identified in the cardiac tissue of epileptic animals through RNA-Seq and liquid chromatography with tandem mass spectrometry-based proteomic analysis, respectively. The network analysis revealed seven critical genes-STAT3, Myc, Fos, Erbb2, Erbb3, Notch1, and Mapk8-that could play a role in seizure-mediated cardiac changes. The LC-MS/MS analysis supported the activation of the transforming growth factor ß (TGF-ß) pathway in the heart of epileptic animals. Furthermore, our gene and protein expression studies established a key role of STAT3, Erbb, and Mapk8 to develop cardiac changes linked with recurrent seizures. SIGNIFICANCE: The present multi-omics study identified STAT3, Mapk8, and Erbb as key regulators involved in seizure-associated cardiac changes. It provided a deeper understanding of molecular, cellular, and network-level operations of the identified regulators that lead to cardiac changes in epilepsy.

Umbelliferone attenuates glycerol-induced myoglobinuric acute kidney injury through peroxisome proliferator-activated receptor-γ agonism in rats.

Rhabdomyolysis is a clinical syndrome caused by damage to skeletal muscle, which consequently releases breakdown products into circulation and causes acute kidney injury (AKI) in humans. Intramuscular injection of glycerol mimics rhabdomyolysis and associated AKI. In this study, we explored the role of umbelliferone against glycerol-induced AKI in rats. Kidney function was assessed by measuring serum creatinine, urea, electrolytes, and microproteinuria. Renal oxidative stress was quantified using thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione assay. Renal histological changes were determined using periodic acid Schiff and hematoxylin-eosin staining, and immunohistology of apoptotic markers (Bax, Bcl-2) was done. Serum creatine kinase was quantified to assess glycerol-induced muscle damage. Umbelliferone attenuated glycerol-induced change in biochemical parameters, oxidative stress, histological alterations, and renal apoptosis. Pretreatment with bisphenol A diglycidyl ether, a peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist, attenuated umbelliferone-mediated protection. It is concluded that umbelliferone attenuates glycerol-induced AKI possibly through PPAR-γ agonism in rats.

Stevioside protects against rhabdomyolysis-induced acute kidney injury through PPAR-γ agonism in rats.

We explored the potential role of peroxisome proliferator activated receptor-γ (PPAR-γ) in stevioside-mediated renoprotection using rhabdomyolysis-induced acute kidney injury (AKI) model in rats. Rhabdomyolysis refers to intense skeletal muscle damage, which further causes AKI. Glycerol (50% w/v, 8 ml/kg) was injected intramuscularly in rats to induce rhabdomyolysis. After 24 hr, AKI was demonstrated by quantifying serum creatinine, urea, creatinine clearance, microproteinuria, and electrolytes in rats. Further, oxidative stress was measured by assaying thiobarbituric acid reactive substances, generation of superoxide anion, and reduced glutathione levels. Additionally, serum creatine kinase (CK) level was assayed to determine glycerol-induced muscle damage in rats. Pathological changes in rat kidneys were studied using hematoxylin-eosin and periodic acid Schiff staining. Moreover, the expression of apoptotic markers (Bcl-2, Bax) in rat kidneys was demonstrated by immunohistochemistry. Stevioside (10, 25, and 50 mg/kg) was administered to rats, prior to the induction of AKI. In a separate group, bisphenol A diglycidyl ether (BADGE, 30 mg/kg), a PPAR-γ receptor antagonist was given prior to stevioside administration, which was followed by rhabdomyolysis-induced AKI in rats. The significant alteration in biochemical and histological parameters in rats indicated AKI, which was attenuated by stevioside treatment. Pretreatment with BADGE abrogated stevioside-mediated renoprotection, which is suggestive of the involvement of PPAR-γ in its renoprotective effect. In conclusion, stevioside protects against rhabdomyolysis-induced AKI, which may be attributed to modulation of PPAR-γ expression.

Apigenin reverses behavioural impairments and cognitive decline in kindled mice via CREB-BDNF upregulation in the hippocampus.

Objectives: Apigenin is the most common bioflavonoid known to be biologically active after systemic administration and show multiple pharmacological effects. The present study was designed to explore the role of apigenin in pentylenetetrazole (PTZ) kindling associated cognitive and behavioural impairments in the mouse model. Methods: The animals were kindled by injecting a sub-convulsive dose of PTZ (35 mg/kg) on every alternate day, followed by 20 days treatment with apigenin at two different doses (10 and 20 mg/kg). Seizure severity was assessed on every 5th, 10th, 15th, and 20th day during apigenin treatment after a PTZ injection, followed by analysis of cognitive and behavioural functions. Results: Apigenin treatment displayed insignificant effect on seizure severity in kindled mice at both the tested doses, in comparison to control. However, the treatment showed marked increase in per cent spontaneous alterations and decline in the anxiety index in T-maze and elevated plus maze tests, respectively. Apigenin-treated groups showed significant decrease in immobility period in both forced swim and tail suspension tests, without any change in the total locomotor activity in the open field test. Furthermore, increase in the hippocampus protein expression of brain-derived neurotrophic factor (BDNF), cAMP response element binding protein (CREB), and phosphorylated CREB, with increased serotonin level were also observed in the treated animals. Discussion: The results of the present study showed that apigenin treatment prevents cognitive deficit and reverses behaviour impairments, without altering seizures severity in kindled mice. The observed effects can be attributed to CREB-BDNF upregulation in the hippocampus.

Mycophenolate mofetil contributes to downregulation of the hippocampal interleukin type 2 and 1ß 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-1ß, 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-1ß linked PI3K/AKT/mTOR signaling pathway hyperactivation.

Protective effect on phenytoin-induced cognition deficit in pentylenetetrazol kindled mice: A repertoire of Glycyrrhiza glabra flavonoid antioxidants.

CONTEXT: Glycyrrhiza glabra L. (Febaceae) has been widely used in traditional medicine and scientifically explored for its anticonvulsant and memory improving potential. OBJECTIVE: The objective of this study is to investigate the effect of flavonoid rich fraction of G. glabra root extract against phenytoin-induced cognition deficit in pentylenetetrazol (PTZ) kindled mice. MATERIALS AND METHODS: The ethyl acetate fraction was initially screened in different in vitro free radical scavenging assays. For in vivo studies, the kindled mice in different groups were given 15 d post-treatment with phenytoin (25 mg/kg; p.o.) per se or in combination with varying doses of the fraction (5, 10, and 15 mg/kg; p.o.). Seizure severity score and cognitive functions were accessed using Racine's scale and passive shock avoidance paradigm, respectively on every 5th d after a PTZ challenge dose (35 mg/kg; i.p.). At the end of study, the animals were scarified for cerebral biochemistry. RESULTS: The fraction showed marked antioxidant activity indicated by low IC50 values in DPPH (20.9 µg/mL), nitric oxide radical scavenging (195.2 µg/mL), and capacity of hydrogen peroxide scavenging (3.4 µg/mL) assays. Treatment with phenytoin per se and along with the flavonoid rich fraction showed significant reduction in seizure severity score as compared to vehicle control. The combined-treated groups also showed improved cognitive functions indicated by reduced number of mistakes and increased step-down latency in passive shock avoidance paradigm. CONCLUSION: From the results, it can be concluded that the flavonoid rich fraction in combination with phenytoin reduces seizure severity and improve cognitive functions in PTZ-kindled mice.

Dwindling of cardio damaging effect of isoproterenol by Punica granatum L. peel extract involve activation of nitric oxide-mediated Nrf2/ARE signaling pathway and apoptosis inhibition.

Punica granatum L. (Punicaceae) peel is often considered as a food waste in-spite of its high bioactive metabolite composition. Primarily it is rich in therapeutically active phenolics that act on multiple cellular sites, through diverse mechanisms. Hence, the present study was envisaged to investigate the effect of standardised peel extract of P. granatum against isoproterenol (ISO)-induced myocardial infarction (MI). ISO administration at a dose of 150 mg/kg; s.c., twice at 24 h interval resulted in electrocardiographic abnormalities with increased heart weight and myocardial tissue damage signifying MI. Pretreatment with the extract at 50, 100 and 200 mg/kg; p.o., for 21 days prior to ISO intoxication (30 min prior to intoxication on day 22 and 23) attenuated the observed changes, along with increased myocardial tissue superoxide dismutase activity, reduced glutathione and nitrite levels, and decreased lipid peroxidation. The extract treated groups also showed reduced serum marker enzymes of MI, showing maximum effect at highest tested dose. Immunohistochemical studies revealed increased myocardial expression of nuclear factor erythroid 2-related factor 2 (Nrf2), endothelial nitric oxide synthase (eNOS) and Bcl-2 proteins in the extract treated groups with decreased Bax expression. From the results it can be concluded that the extract pretreatment prevents ISO-induced MI through increased myocardial expression of eNOS, leading to nitric oxide-mediated Nrf2 activation, thus upregulating antioxidant mechanisms, along with inhibition of apoptosis.

Ficus religiosa L. figs--a potential herbal adjuvant to phenytoin for improved management of epilepsy and associated behavioral comorbidities.

Oxidative stress, together with mitochondrial dysfunction, has been reported to be involved in the pathogenesis of epileptogenesis and its associated comorbidities. Phytoflavonoids have shown numerous beneficial ameliorative effects on different neurological disorders by virtue of their antioxidant effect. The present study investigated the effect of flavonoid-rich ethyl acetate fraction of the crude fig extract of Ficus religiosa in combination with phenytoin on seizure severity, depressive behavior, and cognitive deficit in pentylenetetrazol (PTZ)-kindled mice. The flavonoid-rich ethyl acetate fraction of the crude fig extract was found to show significant antioxidant potential in various in vitro free radical scavenging assays. Combined treatment of this fraction (2.5, 5, and 10 mg/kg; i.p.) along with a subeffective dose of phenytoin (15 mg/kg; i.p.) in postkindled animals once daily for fifteen days showed a dose-dependent decrease in the seizure severity score, a decreased number of mistakes, increased step-down latency in passive shock avoidance paradigm, and decreased immobility time in the tail suspension test in comparison with the phenytoin only-treated group. Biochemical investigations of the brain tissue showed amelioration of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) levels, and reduced catalase and acetylcholinesterase (AChE) activities, thereby indicating suppression of oxidative stress. In conclusion, the results of the present study showed the protective effect of the flavonoid-rich fraction of F. religiosa along with a subeffective dose of phenytoin in PTZ-kindling-associated cognitive deficit and depressive behavior with complete suppression of seizures through reduction of oxidative stress, supporting the the need for clinical evaluation of the supplementation of phytoflavonoids along with antiepileptic drugs (AEDs) for management of epilepsy and its psychiatric and cognitive comorbidities.

Phenylthiourea-mediated experimental depigmentation reduces seizurogenic response of pentylenetetrazol in zebrafish larva.

Zebrafish larvae exposed to chemoconvulsants show behavioral seizures and electrographic abnormalities similar to the other mammalian models, making it a potential tool in epilepsy research. During the embryonic stage, zebrafish remains transparent which enables real-time developmental detection and in-situ gene/protein expression. However, pigmentation during the larval stage restricts transparency. Phenylthiourea (1-phenyl-2-thiourea; PTU) is a commonly used pigmentation blocker that maintains larval transparency. It is widely used along with chemoconvulsants to study in situ expressions in epileptic larvae, however, its effect on seizures largely remains unknown. Therefore, in the present study, the effect of PTU-mediated depigmentation was studied on pentylenetetrazol (PTZ)-induced seizures in zebrafish larvae. After spawning, the fish embryos were subjected to standard depigmentation protocol using 0.13 mM PTU. At 7-days post fertilization seizures were induced using 8 mM PTZ. PTU exposure significantly reduced PTZ-mediated hyperactive responses indicated by decreased distance travelled and swimming velocity of the larvae. Furthermore, PTU-exposed depigmented larvae also showed an increase in the latency to the onset of PTZ-mediated clonic-like seizures. The results concluded that PTU depigmentation protocol reduces the seizurogenic response of PTZ, hence its usage for imaging zebrafish larvae must be carefully monitored to avoid erroneous results.

Mitochondrial mechanisms in Cerebral Ischemia-Reperfusion Injury: Unravelling the intricacies.

Cerebral ischemic stroke is a major contributor to physical impairments and premature death worldwide. The available reperfusion therapies for stroke in the form of mechanical thrombectomy and intravenous thrombolysis increase the risk of cerebral ischemia-reperfusion (I-R) injury due to sudden restoration of blood supply to the ischemic region. The injury is manifested by hemorrhagic transformation, worsening of neurological impairments, cerebral edema, and progression to infarction in surviving patients. A complex network of multiple pathological processes has been known to be involved in the pathogenesis of I-R injury. Primarily, 3 major contributors namely oxidative stress, neuroinflammation, and mitochondrial failure have been well studied in I-R injury. A transcription factor, Nrf2 (Nuclear factor erythroid 2-related factor 2) plays a crucial defensive role in resisting the deleterious effects of I-R injury and potentiating the cellular protective mechanisms. In this review, we delve into the critical function of mitochondria and Nrf2 in the context of cerebral I-R injury. We summarized how oxidative stress, neuroinflammation, and mitochondrial anomaly contribute to the pathophysiology of I-R injury and further elaborated the role of Nrf2 as a pivotal guardian of cellular integrity. The review further highlighted Nrf2 as a putative therapeutic target for mitochondrial dysfunction in cerebral I-R injury management.

Effect of saponin fraction from Ficus religiosa on memory deficit, and behavioral and biochemical impairments in pentylenetetrazol kindled mice.

In our previous study, the saponin-rich fraction (SRF) of adventitious root extract of Ficus religiosa L. (Moraceae) was shown to have an anticonvulsant effect in acute animal models of convulsions. The present study was envisaged to study the effect of SRF in the pentylenetetrazol (PTZ) kindling mouse model and its associated depression and cognition deficit. Treatment with the SRF (1, 2 and 4 mg/kg; i.p.) for 15 days in kindled mice significantly decreased seizure severity on days 5, 10 and 15 when challenged with PTZ (35 mg/kg; i.p.). Marked protection against kindling-associated depression was also observed on days 10 and 15 in the SRF-treated groups when tested using the tail-suspension test. However, the SRF treatment failed to protect kindling-associated learning and memory impairments in the passive shock avoidance paradigm. The observed behavioral effects were corroborated with modulation in the levels of noradrenaline, dopamine, serotonin, GABA and glutamate in discrete brain regions.

Protective effect of Nardostachys jatamansi extract against lithium-pilocarpine-induced spontaneous recurrent seizures and associated cardiac irregularities in a rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Nardostachys jatamansi (D.Don) DC. is a perennial herbaceous medicinal plant widely used for the ethnomedical treatment of various ailments. The underground parts of the plants are used in traditional medicine to manage epilepsy and other cardiovascular conditions. AIM OF THE STUDY: The present study was undertaken to investigate the efficacy of a characterized hydroalcoholic extract (NJET) of Nardostachys jatamansi in the lithium-pilocarpine rat model of spontaneous recurrent seizures (SRS) and associated cardiac irregularities. MATERIALS AND METHODS: NJET was prepared by percolation using 80% ethanol. The dried NEJT was subjected to UHPLC-qTOF-MS/MS for chemical characterization. Molecular docking studies were performed using the characterized compounds to understand mTOR interactions. The animals showing SRS following lithium-pilocarpine administration were treated with NJET for 6 weeks. Afterward, seizure severity, cardiac parameters, serum biochemistry, and histopathological parameters were studied. The cardiac tissue was processed for specific protein and gene expression studies. RESULTS: The UHPLC-qTOF-MS/MS characterized 13 compounds in NJET. The identified compounds subjected to molecular docking showed promising binding affinities toward mTOR. There was a dose-dependent decrease in the severity of SRS following the extract administration. A reduction in mean arterial pressure and serum biochemical markers (lactate dehydrogenase and creatine kinase) was also observed following NJET treatment in epileptic animals. Histopathological investigations revealed reduced degenerative changes and decreased fibrosis following the extract treatment. The cardiac mRNA level of Mtor, Rps6, Hif1a, and Tgfb3 was reduced in the extract-treated groups. Further, a similar reduction in the protein expression of p-mTOR and HIF-1α was also observed following NJET treatment in the cardiac tissue. CONCLUSIONS: The results concluded that NJET treatment reduces lithium-pilocarpine-induced recurrent seizures and associated cardiac irregularities via downregulation of the mTOR signalling pathway.

Lithium co-administration with rutin improves post-stroke neurological outcomes via suppressing Gsk-3ß activity in a rat model.

Cerebral ischemic stroke is one of the leading causes of adult disability worldwide. Reperfusion is the only therapeutic option with a lot of side effects. In the current study, we investigated the efficacy of rutin and lithium co-treatment in improving post-stroke neurological outcomes in a transient global cerebral ischemia-reperfusion injury rat model. Middle-aged male rats were subjected to transient global cerebral ischemia-reperfusion. NORT and Y-maze were used to assess the cognitive processes. Lipid peroxidation, protein carbonylation, and nitric oxide assays were performed to study oxidative stress. The excitotoxicity index was calculated by HPLC. Real time-PCR and western blotting were performed to study gene and protein expressions. The co-administration of rutin and lithium improved the overall survival, recognition memory, spatial working memory, and neurological score following cerebral ischemia-reperfusion in rats. Further, a marked decrease in malonaldehyde, protein carbonyls, and nitric oxide levels was observed following combined treatment. The mRNA expression of antioxidant (Hmox1 and Nqo1) and pro-inflammatory (Il2, Il6, and Il1ß) markers were significantly attenuated in the rutin and lithium co-administrated group. The treatment inhibited the Gsk-3ß and maintained a normal pool of the downstream ß-catenin and Nrf2 proteins. The results revealed that co-administration of rutin and lithium had a neuroprotective potential, suggesting it to be a viable treatment to overcome post-stroke deaths and neurological complications.

Chemo-kindling in adult zebrafish alters spatial cognition but not social novelty recognition.

In the past decades, zebrafish have gathered immense attention and importance in the field of neurological sciences. In the case of epilepsy, zebrafish have appeared as a promising acute animal model for the screening and identification of potential antiepileptic molecules. However, the necessity for establishing competent chronic models of epilepsy in zebrafish is apparent. In this regard, recently we developed a chemo-kindling zebrafish model with a better clinical resemblance. In the present study, an attempt to examine the effect of pentylenetetrazole (PTZ)-induced kindling on the cognitive functions of zebrafish was made. In brief, adult zebrafish were repetitively given a sub-effective concentration of PTZ, till the onset of clonic-tonic seizures, entitled as kindled. Thereafter, T-maze test and social recognition memory test were conducted to evaluate spatial memory and social novelty recognition memory of the fish. At the end, both the groups were sacrificed and the brains were isolated to estimate neurotransmitter and gene expression levels. It was observed that PTZ kindling induced spatial cognition deficits and lower social exploration in zebrafish. However, it didn't change the novelty recognition memory of kindled zebrafish. The results of genes and neurotransmitters estimations in the brain also supported the behavioural findings. The results concluded that PTZ kindling alters spatial cognitive functions in adult zebrafish without affecting the social novelty recognition memory.

Role of saponins for the anticonvulsant effect of adventitious roots of Ficus religiosa.

CONTEXT: The adventitious roots of Ficus religiosa L. (Moraceae) have been extensively used in traditional medicine for treatment of several disorders, including epilepsy. OBJECTIVE: To investigate the possible anticonvulsant effect of the adventitious roots of Ficus religiosa, and to find the biologically active fraction, to substantiate its traditional use in epilepsy. METHODS: The hydroethanolic extract of adventitious roots (5, 10, and 20 mg/kg; i.p.) of Ficus religiosa and its different fractions (hexane, chloroform, ethyl acetate, butanol, aqueous, saponins-rich, and saponins-lacking) at a dose equivalent to 20 mg/kg of the extract were administered 30 min prior to the induction of maximal electroshock (MES) and pentylenetetrazol (PTZ) convulsions. Duration of tonic hind-limb extension (THLE) and latency to clonic convulsions were noted in MES and PTZ tests, respectively. Neurotoxicity was assessed using rotarod test. RESULTS: Treatment with the root extract (5, 10, and 20 mg/kg; i.p.), butanolic (6 mg/kg; i.p.) and saponins-rich fractions (3.4 mg/kg; i.p.) significantly (p < 0.05) decreased the duration of THLE in MES test, as compared to control. The same treatment also significantly (p < 0.05) increased the latency to PTZ-induced clonic convulsions in comparison to control. The other fractions were found to be ineffective. The root extract and its active fractions at their effective doses showed no neurotoxic effects. CONCLUSION: The present study concluded that the hydroethanolic extract of adventitious roots of Ficus religiosa has anticonvulsant activity. Retention of anticonvulsant effect in the saponins-rich fraction-treated animals indicated the role of saponins for the activity.

Dimension learning based chimp optimizer for energy efficient wireless sensor networks.

Wireless sensors are the basic requisite of today's smart infrastructure based on internet of things (IoTs), 5G and wireless sensor networks (WSNs). WSNs are widely used in industrial applications, precision agriculture and animal tracking systems, environment monitoring, smart grids, energy control systems, smart buildings and entertainment industry etc. The distributed and dynamic scheme of WSNs establishes very unique demands in developing clustering and routing protocols. In order to meet the demand of efficient WSNs, most important requirement is energy management and extension of network lifetime. So energy constraints issue is one of the most emerging area for research to reduce the complexity of network functioning. Due to the complexity of this task we need more robustness optimizer algorithms which can tackle these types of tasks. In this article we are trying to develop one improved version of chimp optimizer for energy constraint issues. In this modification have been integrated the chimp optimizer with dimension learning based hunting (DLH) search technique, known as Improved Chimp Optimizer Algorithm (IChoA). Here the DLH search strategy helps in maintaining diversity and improves the balance between exploitation and exploration. To compute the robustness in solving the optimizer issues, IChoA has been tested on 29-CEC-2017 test suites and energy constraint issues. Experimental solutions obtained by proposed methods are verified with recent methods. All simulation shows that the IChoA method can be most effective in solving the standard complex suites and energy constraint issues.

Insights into the Cellular Interactions and Molecular Mechanisms of Ketogenic Diet for Comprehensive Management of Epilepsy.

A high-fat diet with appropriate protein and low carbohydrate content, widely known as the ketogenic diet (KD), is considered as an effective non-pharmacotherapeutic treatment option for certain types of epilepsies. Several preclinical and clinical studies have been carried out to elucidate its mechanism of antiepileptic action. Ketone bodies produced after KD's breakdown interact with cellular excito-inhibitory processes and inhibit abnormal neuronal firing. The generated ketone bodies decrease glutamate release by inhibiting the vesicular glutamate transporter 1 and alter the transmembrane potential by hyperpolarization. Apart from their effect on the well-known pathogenic mechanisms of epilepsy, some recent studies have shown the interaction of KD metabolites with novel neuronal targets, particularly adenosine receptors, adenosine triphosphate-sensitive potassium channel, mammalian target of rapamycin, histone deacetylase, hydroxycarboxylic acid receptors, and the NLR family pyrin domain containing 3 inflammasomes to suppress seizures. The role of KD in augmenting gut microbiota as a potential mechanism for epileptic seizure suppression has been established. Furthermore, some recent findings also support the beneficial effect of KD against epilepsy- associated comorbidities. Despite several advantages of the KD in epilepsy management, its use is also associated with a wide range of side effects. Hypoglycemia, excessive ketosis, acidosis, renal stones, cardiomyopathies, and other metabolic disturbances are the primary adverse effects observed with the use of KD. However, in some recent studies, modified KD has been tested with lesser side effects and better tolerability. The present review discusses the molecular mechanism of KD and its role in managing epilepsy and its associated comorbidities.

R-α-Lipoic Acid Conjugated to d-α-Tocopherol Polyethylene Glycol 1000 Succinate: Synthesis, Characterization, and Effect on Antiseizure Activity.

α-Lipoic acid (LA), a dithiol micronutrient, acts as a vital cofactor in various cellular catabolic reactions and is also known as a universal antioxidant. The therapeutic efficacy of LA is compromised by a poor aqueous solubility as well as a short half-life. In the present study, LA was conjugated to d-α-tocopherol polyethylene glycol succinate (TPGS) using carbodiimideacid-alcohol coupling reaction. The synthesized conjugate (TPGS-LA) was characterized using 1H and 13C nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FT-IR), UV-vis spectroscopy, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The TPGS-LA conjugate was demonstrated to be biocompatible and to have better anticonvulsion activity as compared to native LA in pentylenetetrazol (PTZ)-induced convulsions in zebrafish. Moreover, zebrafish larvae pretreated with TPGS-LA conjugate demonstrated a significant (p < 0.05) reduction of protein carbonylation levels and downregulation of c-fos expression during seizures as compared to native LA. Conclusively, the present findings demonstrate that the TPGS-LA conjugate can be a promising approach for the delivery of LA.