Fisetin-loaded chitosan nanoparticles ameliorate pilocarpine-induced temporal lobe epilepsy and associated neurobehavioral alterations in mice: Role of ROS/TNF-α-NLRP3 inflammasomes pathway.

Fisetin has displayed potential as an anticonvulsant in preclinical studies yet lacks clinical validation. Challenges like low solubility and rapid metabolism may limit its efficacy. This study explores fisetin-loaded chitosan nanoparticles (NP) to address these issues. Using a murine model of pilocarpine-induced temporal lobe epilepsy, we evaluated the anticonvulsant and neuroprotective effects of fisetin NP. Pilocarpine-induced seizures and associated neurobehavioral deficits were assessed after administering subtherapeutic doses of free fisetin and fisetin NP. Changes in ROS, inflammatory cytokines, and NLRP3/IL-18 expression in different brain regions were estimated. The results demonstrate that the fisetin NP exerts protection against seizures and associated depression-like behavior and memory impairment. Furthermore, biochemical, and histological examinations supported behavioral findings suggesting attenuation of ROS/TNF-α-NLRP3 inflammasome pathway as a neuroprotective mechanism of fisetin NP. These findings highlight the improved pharmacodynamics of fisetin using fisetin NP against epilepsy, suggesting a promising therapeutic approach against epilepsy and associated behavioral deficits.

Harnessing Therapeutic Potentials of Biochanin A in Neurological Disorders: Pharmacokinetic and Pharmacodynamic Overview.

Biochanin A, an isoflavone flavonoid with estrogenic activity, is naturally found in red clover and other legumes. It possesses a wide range of pharmacological properties, including antioxidant, anti-inflammatory, anti-apoptotic, neuroprotective, and anticancer effects. In recent years, a growing body of pre-clinical research has focused on exploring the therapeutic potential of biochanin A in various neurological disorders, such as Alzheimer's and Parkinson's disease, multiple sclerosis, epilepsy, ischemic brain injury, gliomas, and neurotoxicity. This comprehensive review aims to shed light on the underlying molecular mechanisms that contribute to the neuroprotective role of biochanin A based on previous pre-clinical studies. Furthermore, it provides a detailed overview of the protective effects of biochanin A in diverse neurological disorders. The review also addresses the limitations associated with biochanin A administration and discusses different approaches employed to overcome these challenges. Finally, it highlights the future opportunities for translating biochanin A from pre-clinical research to clinical studies while also considering its commercial viability as a dietary supplement or a potential treatment for various diseases.

Formulation and Characterization of Silibinin Entrapped Nano-Liquid Crystals for Activity against Aß1-42 Neurotoxicity in In-Vivo Model.

Silibinin (SIL) Encapsulated Nanoliquid Crystalline (SIL-NLCs) particles were prepared to study neuroprotective effect against amyloid beta (Aß1-42) neurotoxicity in Balb/c mice model. Theses NLCs were prepared through hot emulsification and probe sonication technique. The pharmacodynamics was investigatigated on Aß1-42 intracerebroventricular (ICV) injected Balb/c mice. The particle size, zeta potential and drug loading were optimized to be 153 ± 2.5 nm, -21 mV, and 8.2%, respectively. Small angle X-ray (SAXS) and electron microscopy revealed to crystalline shape of SIL-NLCs. Thioflavin T (ThT) fluroscence and circular dichroism (CD) technique were employed to understand monomer inhibition effect of SIL-NLCs on Aß1-4. In neurobehavioral studies, SIL-NLCs exhibited enhanced mitigation of memory impairment induced on by Aß1-42 in T-maze and new object recognition test (NORT). Whereas biochemical and histopathological estimation of brain samples showed reduction in level of Aß1-42 aggregate, acetylcholine esterase (ACHE) and reactive oxygen species (ROS). SIL-NLCs treated animal group showed higher protection against Aß1-42 toxicity compared to free SIL and Donopezil (DPZ). Therefore SIL-NLCs promises great prospect in neurodegenerative diseases such as Alzheimer's disease.

The microbiome-gut-brain axis in epilepsy: pharmacotherapeutic target from bench evidence for potential bedside applications.

The gut-brain axis augments the bidirectional communication between the gut and brain and modulates gut homeostasis and the central nervous system through the hypothalamic-pituitary-adrenal axis, enteroendocrine system, neuroendocrine system, inflammatory and immune pathways. Preclinical and clinical reports showed that gut dysbiosis might play a major regulatory role in neurological diseases such as epilepsy, Parkinson's, multiple sclerosis, and Alzheimer's disease. Epilepsy is a chronic neurological disease that causes recurrent and unprovoked seizures, and numerous risk factors are implicated in developing epilepsy. Advanced consideration of the gut-microbiota-brain axis can reduce ambiguity about epilepsy pathology, antiepileptic drugs, and effective therapeutic targets. Gut microbiota sequencing analysis reported that the level of Proteobacteria, Verrucomicrobia, Fusobacteria, and Firmicutes was increased and the level of Actinobacteria and Bacteroidetes was decreased in epilepsy patients. Clinical and preclinical studies also indicated that probiotics, ketogenic diet, faecal microbiota transplantation, and antibiotics can improve gut dysbiosis and alleviate seizure by enhancing the abundance of healthy biota. This study aims to give an overview of the connection between gut microbiota, and epilepsy, how gut microbiome changes may cause epilepsy, and whether gut microbiome restoration could be used as a treatment for epilepsy.

Promising biomarkers and therapeutic targets for the management of Parkinson's disease: recent advancements and contemporary research.

Parkinson's disease (PD) is one of the progressive neurological diseases which affect around 10 million population worldwide. The clinical manifestation of motor symptoms in PD patients appears later when most dopaminergic neurons have degenerated. Thus, for better management of PD, the development of accurate biomarkers for the early prognosis of PD is imperative. The present work will discuss the potential biomarkers from various attributes covering biochemical, microRNA, and neuroimaging aspects (α-synuclein, DJ-1, UCH-L1, ß-glucocerebrosidase, BDNF, etc.) for diagnosis, recent development in PD management, and major limitations with current and conventional anti-Parkinson therapy. This manuscript summarizes potential biomarkers and therapeutic targets, based on available preclinical and clinical evidence, for better management of PD.

Flavonoids as promising anticancer therapeutics: Contemporary research, nanoantioxidant potential, and future scope.

Flavonoids are natural polyphenolic compounds considered safe, pleiotropic, and readily available molecules. It is widely distributed in various food products such as fruits and vegetables and beverages such as green tea, wine, and coca-based products. Many studies have reported the anticancer potential of flavonoids against different types of cancers, including solid tumors. The chemopreventive effect of flavonoids is attributed to various mechanisms, including modulation of autophagy, induction of cell cycle arrest, apoptosis, and antioxidant defense. Despite of significant anticancer activity of flavonoids, their clinical translation is limited due to their poor biopharmaceutical attributes (such as low aqueous solubility, limited permeability across the biological membranes (intestinal and blood-brain barrier), and stability issue in biological systems). A nanoparticulate system is an approach that is widely utilized to improve the biopharmaceutical performance and therapeutic efficacy of phytopharmaceuticals. The present review discusses the significant anticancer potential of promising flavonoids in different cancers and the utilization of nanoparticulate systems to improve their nanoantioxidant activity further to enhance the anticancer activity of loaded promising flavonoids. Although, various plant-derived secondary metabolites including flavonoids have been recommended for treating cancer, further vigilant research is warranted to prove their translational values.

CRISPR-based point-of-care diagnostics incorporating Cas9, Cas12, and Cas13 enzymes advanced for SARS-CoV-2 detection.

An outbreak of the novel beta coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first came to light in December 2019, which has unfolded rapidly and turned out to be a global pandemic. Early prognosis of viral contamination involves speedy intervention, disorder control, and good-sized management of the spread of disease. Reverse transcription-polymerase chain reaction, considered the gold standard test for detecting nucleic acids and pathogen diagnosis, provides high sensitivity and specificity. However, reliance on high-priced equipped kits, associated reagents, and skilled personnel slow down sickness detection. Lately, the improvement of clustered regularly interspaced short palindromic repeat (CRISPR)-Cas (CRISPR-associated protein)-based diagnostic systems has reshaped molecular diagnosis due to their low cost, simplicity, speed, efficiency, high sensitivity, specificity, and versatility, which is vital for accomplishing point-of-care diagnostics. We reviewed and summarized CRISPR-Cas-based point-of-care diagnostic strategies and research in these paintings while highlighting their characteristics and challenges for identifying SARS-CoV-2.

Neuroprotective potential of cinnamon and its metabolites in Parkinson's disease: Mechanistic insights, limitations, and novel therapeutic opportunities.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder with obscure etiology and no disease-modifying therapy to date. Hence, novel, safe, and low cost-effective approaches employing medicinal plants are currently receiving increased attention. A growing body of evidence has revealed that cinnamon, being widely used as a spice of unique flavor and aroma, may exert neuroprotective effects in several neurodegenerative diseases, including PD. In vitro evidence has indicated that the essential oils of Cinnamomum species, mainly cinnamaldehyde and sodium benzoate, may protect against oxidative stress-induced cell death, reactive oxygen species generation, and autophagy dysregulation, thus acting in a potentially neuroprotective manner. In vivo evidence has demonstrated that oral administration of cinnamon powder and sodium benzoate may protect against dopaminergic cell death, striatal neurotransmitter dysregulation, and motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models of PD. The underlying mechanisms of its action include autophagy regulation, antioxidant effects, upregulation of Parkin, DJ-1, glial cell line-derived neurotrophic factor, as well as modulation of the Toll-like receptors/nuclear factor-κB pathway and inhibition of the excessive proinflammatory responses. In addition, in vitro and in vivo studies have shown that cinnamon extracts may affect the oligomerization process and aggregation of α-synuclein. Herein, we discuss recent evidence on the novel therapeutic opportunities of this phytochemical against PD, indicating additional mechanistic aspects that should be explored and potential obstacles/limitations that need to be overcome for its inclusion in experimental PD therapeutics.

Neuroprotective potential of cinnamon and its metabolites in Parkinson's disease: Mechanistic insights, limitations, and novel therapeutic opportunities.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder with obscure etiology and no disease-modifying therapy to date. Hence, novel, safe, and low cost-effective approaches employing medicinal plants are currently receiving increased attention. A growing body of evidence has revealed that cinnamon, being widely used as a spice of unique flavor and aroma, may exert neuroprotective effects in several neurodegenerative diseases, including PD. In vitro evidence has indicated that the essential oils of Cinnamomum species, mainly cinnamaldehyde and sodium benzoate may protect against oxidative stress-induced cell death, reactive oxygen species generation, and autophagy dysregulation, thus acting in a potentially neuroprotective manner. In vivo evidence has demonstrated that oral administration of cinnamon powder and sodium benzoate may protect against dopaminergic cell death, striatal neurotransmitter dysregulation, and motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models of PD. The underlying mechanisms of its action include autophagy regulation, antioxidant effects, upregulation of Parkin, DJ-1, glial cell line-derived neurotrophic factor, as well as modulation of the TLR/NF-κB pathway and inhibition of the excessive proinflammatory responses. In addition, in vitro and in vivo studies have shown that cinnamon extracts may affect the oligomerization process and aggregation of α-synuclein. Herein, we discuss recent evidence on the novel therapeutic opportunities of this phytochemical against PD, indicating additional mechanistic aspects that should be explored, and potential obstacles/limitations that need to be overcome, for its inclusion in experimental PD therapeutics.

PTZ kindling model for epileptogenesis, refractory epilepsy, and associated comorbidities: relevance and reliability.

Pentylenetetrazole (PTZ)-induced seizure is one of the gold standard mouse models for rapid evaluation of novel anticonvulsants. Synchronically, PTZ induced kindling in mice is also a simple and well accepted model of chronic epilepsy. PTZ kindling has been explored for studying epileptogenesis, epilepsy-associated comorbidities, and refractory epilepsy. This review summarizes the potential of PTZ kindling in mice and its modifications for its face, construct, and predictive validity to screen antiepileptogenic drugs, combined or add on novel and safe therapies for treatment of epilepsy-associated depression and cognitive impairment as well as effective interventions for pharmacoresistant epilepsy.

Neuroinflammation in neurological disorders: pharmacotherapeutic targets from bench to bedside.

Neuroinflammation is one of the host defensive mechanisms through which the nervous system protects itself from pathogenic and or infectious insults. Moreover, neuroinflammation occurs as one of the most common pathological outcomes in various neurological disorders, makes it the promising target. The present review focuses on elaborating the recent advancement in understanding molecular mechanisms of neuroinflammation and its role in the etiopathogenesis of various neurological disorders, especially Alzheimer's disease (AD), Parkinson's disease (PD), and Epilepsy. Furthermore, the current status of anti-inflammatory agents in neurological diseases has been summarized in light of different preclinical and clinical studies. Finally, possible limitations and future directions for the effective use of anti-inflammatory agents in neurological disorders have been discussed.

Neuroprotective Potential of Chrysin: Mechanistic Insights and Therapeutic Potential for Neurological Disorders.

Chrysin, a herbal bioactive molecule, exerts a plethora of pharmacological effects, including anti-oxidant, anti-inflammatory, neuroprotective, and anti-cancer. A growing body of evidence has highlighted the emerging role of chrysin in a variety of neurological disorders, including Alzheimer's and Parkinson's disease, epilepsy, multiple sclerosis, ischemic stroke, traumatic brain injury, and brain tumors. Based on the results of recent pre-clinical studies and evidence from studies in humans, this review is focused on the molecular mechanisms underlying the neuroprotective effects of chrysin in different neurological diseases. In addition, the potential challenges, and opportunities of chrysin's inclusion in the neurotherapeutics repertoire are critically discussed.

Role of curcumin and its nanoformulations in neurotherapeutics: A comprehensive review.

Curcumin, a dietary polyphenol and major constituent of Curcuma longa (Zingiberaceae), is extensively used as a spice in Asian countries. For ages, turmeric has been used in traditional medicine systems to treat various diseases, which was possible because of its anti-inflammatory, antioxidant, anticancerous, antiepileptic, antidepressant, immunomodulatory, neuroprotective, antiapoptotic, and antiproliferative effects. Curcumin has potent antioxidant, anti-inflammatory, antiapoptotic, neurotrophic activities, which support its plausible neuroprotective effects in neurodegenerative disease. However, there is limited information available regarding the clinical efficacy of curcumin in neurodegenerative cases. The low oral bioavailability of curcumin may be speculated as a plausible factor that limits its effects in humans. Therefore, utilization of several approaches for the enhancement of bioavailability may improve clinical outcomes. Furthermore, the use of nanotechnology and a targeted drug delivery system may improve the bioavailability of curcumin. The present review is designed to summarize the molecular mechanisms pertaining to the neuroprotective effects of curcumin and its nanoformulations.

Effect of hesperidin on fluoride-induced neurobehavioral and biochemical changes in rats.

Fluoride is the second largest contaminant of drinking water. Fluoride toxicity is a major concern in the endemic areas where a high amount of fluoride is present in ground water. Oxidative stress has been proposed to be one of the mechanisms of fluoride-induced toxicity. Antioxidant-rich food has been found to alleviate fluoride-induced toxicity. Therefore, in this study, we have examined the effect of hesperidin on fluoride-induced neurobehavioral changes in rats. In the current study, male Sprague-Dawley rats were exposed to sodium fluoride through drinking water (120 ppm). Hesperidin (200 mg kg-1 d-1 ; per os) was administered either alone or in combination with fluoride-containing drinking water. Bisphinol A diglycidyl ether (BADGE) was used as peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist and was administered (10 mg kg-1 d-1 ; intraperitoneal injection) with/without hesperidin along with fluoride-containing drinking water. The behavioral changes in the animals were assessed by analyzing rotarod test, novel object recognition test, and forced swim test (FST). After 8 weeks, animals were killed to isolate blood and brain for monitoring biochemical changes. The 8-week exposure of fluoride resulted in motor impairment as observed with reduced fall time in rotarod test, memory impairment as observed with reduced preference index in novel object recognition test, and depression-like behavior as observed with reduced mobility index in the FST. Treatment with hesperidin improved neurobehavioral impairment along with restoration in brain biochemical changes (ie, acetylcholinesterase activity and antioxidant and oxidative stress parameters). The protective effect of hesperidin was reversed by coadministration of BADGE. The neuroprotective effect of hesperidin appears to be contributed through PPAR-γ receptor.

Rational approaches for toxicological assessments of nanobiomaterials.

The nanobiomaterials display unique and distinguished usefulness in day-to-day life. The application of nanobiomaterials is being utilized in several segments, including semiconductor industries, cosmetics, and medicines. Alongside their usefulness these nanobiomaterials have potential toxicity which may limit it's further use. As there is sparse information on toxicological facets of nanomaterials available, a proactive approach for evaluation of potential risk of nanobiomaterials should be exercised. This review explains the potential mechanism of nanobiomaterials toxicity and rational approaches for selection of protocols to study toxicity of nanobiomaterials.

Revealing Medicinal Plants That Are Useful for the Comprehensive Management of Epilepsy and Associated Comorbidities through In Silico Mining of Their Phytochemical Diversity.

In silico techniques in drug discovery may rationalise and speed up the identification of lead molecules from nature. Drug discovery from medicinal plants has mostly been confined to indications in accordance with their ethnical use only. However, the availability of multiple phytoconstituents in medicinal plants suggests that these may be much more useful beyond their traditional uses and in the management of chronic diseases, along with their comorbidities. In this study, the computer programmes PASS and PharmaExpert were used to reveal the medicinal plants useful in the comprehensive management of epilepsy and associated psychiatric disorders based on the pleiotropic effects predicted for their phytoconstituents. In silico analysis revealed that seven of 50 medicinal plants from traditional Indian medicine possessed the desired pleiotropic effect, i.e., anticonvulsant, antidepressant, and nootropic activities. The majority of phytoconstituents from Passiflora incarnata were concurrently predicted to have the desired pleiotropic effects. Therefore, P. incarnata was pharmacologically validated using the pentylenetetrazole kindling mouse model. Behavioural and neurochemical evaluations confirmed the ameliorative role of P. incarnata in epilepsy and the associated depression and memory deficit. The pharmacological findings from this study propose that PASS and PharmaExpert may serve as good tools for the optimisation of the selection of plants based on their phytoconstituents for the treatment of different ailments, even beyond their traditional use.

Comparative behavioral and neurochemical analysis of phenytoin and valproate treatment on epilepsy induced learning and memory deficit: Search for add on therapy.

Our previous work demonstrated, chronic epilepsy affects learning and memory of rodents along with peculiar neurochemical changes in discrete brain parts. Most commonly used antiepileptic drugs (phenytoin and sodium valproate) also worsen learning and memory in the patients with epilepsy. Therefore this study was designed to carry out comparison of behavioral and neurochemical changes with phenytoin and sodium valproate treatment in pentylenetetrazole-kindling induced learning and memory deficit to devise add on therapy for this menace. For the experimental epilepsy, animals were kindled using PTZ (35 mg/kg; i.p., at 48 ± 2 h intervals) and successful kindled animals were involved in the study. These kindled animals were treated with saline, phenytoin (30 mg/kg/day, i.p.) and sodium valproate (300 mg/kg/day, i.p.) for 20 days. These animals were challenged with PTZ challenging dose (35 mg/kg) on day 5, 10, 15 and 20 to evaluate the effect on seizure severity score on different days. Effect on learning and memory was evaluated using elevated plus maze and passive shock avoidance paradigm. On day 20, after behavioral evaluations, animals were sacrificed to analyze glutamate, GABA, norepinephrine, dopamine, serotonin, total nitrite level and acetylcholinesterase level in cortex and hippocampus. Behavioral evaluations suggested that phenytoin and sodium valproate treatment significantly reduced seizure severity in the kindled animals, while sodium valproate treatment controls seizures with least memory deficit in comparison to phenytoin. Neurochemical findings revealed that elevated cortical acetylcholinesterase level could be one of the responsible factors leading to memory deficit in phenytoin treated animals. However sodium valproate treatment reduced cortical acetylcholinesterase level and had least debilitating consequences on memory deficit. Therefore, attenuation of elevated AChE activity can be one of add-on approach for management of memory deficit associated with conventional AEDs.

Psychoneurochemical investigations to reveal neurobiology of memory deficit in epilepsy.

Pentylenetetrazole-kindling induced memory deficit has been validated in our previous study. The present study attempts a neurochemical investigation to reveal possible targets for treatment of memory deficit associated with pentylenetetrazole-kindling. Kindling was induced by administering subconvulsive dose of pentylenetetrazole (35 mg/kg; i.p.) at an interval of 48 ± 2 h. Successfully kindled animals were divided into two groups (interictal and postictal group), while non-kindled (naive) animals served as naïve group. In postictal group, animals were challenged with pentylenetetrazole (35 mg/kg) on days 5, 10, 15 and 20. Learning and memory were evaluated in all experimental groups using elevated plus maze and passive shock avoidance paradigm on days 5, 10, 15 and 20. After behavioral evaluations on day 20, all animals were sacrificed to remove their brains. Neurochemical (glutamate, GABA, norepinephrine, dopamine and serotonin) changes and acetylcholinesterase activity and total nitrite level were estimated using HPLC-FD methods and microplate reader method respectively, in discrete brain parts. The results of the neurochemical estimation demonstrated the imbalance in excitatory/inhibitory tone, reduction in monoamine level, elevated nitrosative and acetylcholinesterase activity in the cortex and hippocampus, as responsible factors for the pathobiology of learning and memory deficit in epilepsy. Restoration of these changes may be targeted for the management of memory deficit in epileptic patients.

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.

Bioactive Flavonoids: A Comparative Overview of the Biogenetic and Chemical Synthesis Approach.

Flavonoids are natural polyphenolic compounds and constitute a major class of plant secondary metabolites. To date, structures of more than 10,000 different flavonoids have been elucidated, and most of them are present in cells and tissues of plant parts. Flavonoids have been reported to exert multiple physiological activities and are also consumed as dietary supplements. Flavonoids have been extensively explored as anticancer, anti-inflammatory, antidiabetic, antirheumatic, antioxidant, antimalarial, neuroprotective, cardioprotective, anti-angiogenic, and antiproliferative agents. Most of the flavonoids are biosynthesized in plants via the phenylpropanoid pathway. However, they are associated with some limitations. Chemical synthesis is an alternative strategy to improve the yield and obtain purified products but is hampered by drawbacks, such as intolerance to stressful lab conditions. Pharmacokinetics is the rate-limiting step defining the bioavailability and metabolism of flavonoids, though greatly influenced by their chemical structure. However, nanoformulation is an emerging technique to improve biopharmaceutical fate and achieve target drug delivery. Thus, much attention should be given to identifying other possible chemical approaches for synthesizing flavonoids and improving their pharmacokinetic profiling, hence potentiating their efficacy in clinic.