Role of Calcitriol and Vitamin D Receptor (VDR) Gene Polymorphisms in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by amyloid beta (Aß) buildup and neuronal degeneration. An association between low serum vitamin D levels and an increased risk of AD has been reported in several epidemiological studies. Calcitriol (1,25-dihydroxycholecalciferol) is the active form of vitamin D, and is generated in the kidney and many other tissues/organs, including the brain. It is a steroid hormone that regulates important functions like calcium/phosphorous levels, bone mineralization, and immunomodulation, indicating its broader systemic significance. In addition, calcitriol confers neuroprotection by mitigating oxidative stress and neuroinflammation, promoting the clearance of Aß, myelin formation, neurogenesis, neurotransmission, and autophagy. The receptors to which calcitriol binds (vitamin D receptors; VDRs) to exert its effects are distributed over many organs and tissues, representing other significant roles of calcitriol beyond sustaining bone health. The biological effects of calcitriol are manifested through genomic (classical) and non-genomic actions through different pathways. The first is a slow genomic effect involving nuclear VDR directly affecting gene transcription. The association of AD with VDR gene polymorphisms relies on the changes in vitamin D consumption, which lowers VDR expression, protein stability, and binding affinity. It leads to the altered expression of genes involved in the neuroprotective effects of calcitriol. This review summarizes the neuroprotective mechanism of calcitriol and the role of VDR polymorphisms in AD, and might help develop potential therapeutic strategies and markers for AD in the future.

Black Pepper (Piper nigrum) Alleviates Oxidative Stress, Exerts Potential Anti-Glycation and Anti-AChE Activity: A Multitargeting Neuroprotective Agent against Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) are a family of disorders that cause progressive structural and functional degeneration of neurons. Among all the organs in the body, the brain is the one that is the most affected by the production and accumulation of ROS. Various studies have shown that an increase in oxidative stress is a common pathophysiology for almost all NDs, which further affects various other pathways. The available drugs lack the wide spectrum necessary to confront these complexities altogether. Hence, a safe therapeutic approach to target multiple pathways is highly desirable. In the present study, the hexane and ethyl acetate extracts of Piper nigrum (black pepper), an important spice, were evaluated for their neuroprotective potential in hydrogen peroxide-induced oxidative stress in human neuroblastoma cells (SH-SY5Y). The extracts were also subjected to GC/MS to identify the important bioactives present. The extracts exhibited neuroprotection by significantly decreasing the oxidative stress and restoring the mitochondrial membrane potential in the cells. Additionally, the extracts displayed potent anti-glycation and significant anti-Aß fibrilization activities. The extracts were competitive inhibitors of AChE. The multitarget neuroprotective mechanism displayed by Piper nigrum indicates it as a potential candidate in the treatment of NDs.

Multi-Targeting Neuroprotective Effects of Syzygium aromaticum Bud Extracts and Their Key Phytocompounds against Neurodegenerative Diseases.

Alzheimer's disease (AD) is a neurodegenerative disease that causes a gradual loss of normal motor and cognitive function. The complex AD pathophysiology involves various factors such as oxidative stress, neuroinflammation, amyloid-beta (Aß) aggregation, disturbed neurotransmission, and apoptosis. The available drugs suffer from a range of side effects and are not able to cover different aspects of the disease. Therefore, finding a safer therapeutic approach that can affect multiple targets at a time is highly desirable. In the present study, the underlying neuroprotective mechanism of an important culinary spice, Syzygium aromaticum (Clove) extract, and major bioactive compounds were studied in hydrogen peroxide-induced oxidative stress in human neuroblastoma SH-SY5Y cell lines as a model. The extracts were subjected to GC-MS to identify important bioactive components. The extracts and key bio-actives reduced reactive oxygen species (ROS), restored mitochondrial membrane potential (MMP), and provided neuroprotection from H2O2-induced oxidative stress in cell-based assays due to the antioxidant action. They also reduced lipid peroxidation significantly and restored GSH content. Clove extracts have also displayed anti-acetylcholinesterase (AChE) activity, anti-glycation potential, and Aß aggregation/fibrilization inhibition. The multitarget neuroprotective approach displayed by Clove makes it a potential candidate for AD drug development.

Trachyspermum ammi Bioactives Promote Neuroprotection by Inhibiting Acetylcholinesterase, Aß-Oligomerization/Fibrilization, and Mitigating Oxidative Stress In Vitro.

Neurodegenerative diseases (NDs) are a large category of progressive neurological disorders with diverse clinical and pathological characteristics. Among the NDs, Alzheimer's disease (AD) is the most widespread disease, which affects more than 400 million people globally. Oxidative stress is evident in the pathophysiology of nearly all NDs by affecting several pathways in neurodegeneration. No single drug can manage multi-faceted diseases like NDs. Therefore, an alternative therapeutic strategy is required, which can affect several pathophysiological pathways at a time. To achieve this aim, hexane and ethyl acetate extract from Trachyspermum ammi (Carom) were prepared, and GC/MS identified the bioactive compounds. For the cell-based assays, oxidative stress was induced in SH-SY5Y neuroblastoma cells using hydrogen peroxide to evaluate the neuroprotective potential of the Carom extracts/bioactives. The extracts/bioactives provided neuroprotection in the cells by modulating multiple pathways involved in neurodegeneration, such as alleviating oxidative stress and mitochondrial membrane potential. They were potent inhibitors of acetylcholine esterase enzymes and displayed competitive/mixed-type inhibition. Additionally, anti-Aß1-42 fibrilization/oligomerization and anti-glycation activities were also analyzed. The multi-faceted neuroprotection shown via Carom/Carvacrol makes it a prospective contender in drug development for NDs.

Unique Bioactives from Zombie Fungus (Cordyceps) as Promising Multitargeted Neuroprotective Agents.

Cordyceps, also known as "zombie fungus", is a non-poisonous mushroom that parasitizes insects for growth and development by manipulating the host system in a way that makes the victim behave like a "zombie". These species produce promising bioactive metabolites, like adenosine, ß-glucans, cordycepin, and ergosterol. Cordyceps has been used in traditional medicine due to its immense health benefits, as it boosts stamina, appetite, immunity, longevity, libido, memory, and sleep. Neuronal loss is the typical feature of neurodegenerative diseases (NDs) (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS)) and neurotrauma. Both these conditions share common pathophysiological features, like oxidative stress, neuroinflammation, and glutamatergic excitotoxicity. Cordyceps bioactives (adenosine, N6-(2-hydroxyethyl)-adenosine, ergosta-7, 9 (11), 22-trien-3ß-ol, active peptides, and polysaccharides) exert potential antioxidant, anti-inflammatory, and anti-apoptotic activities and display beneficial effects in the management and/or treatment of neurodegenerative disorders in vitro and in vivo. Although a considerable list of compounds is available from Cordyceps, only a few have been evaluated for their neuroprotective potential and still lack information for clinical trials. In this review, the neuroprotective mechanisms and safety profile of Cordyceps extracts/bioactives have been discussed, which might be helpful in the identification of novel potential therapeutic entities in the future.

Prion therapeutics: Lessons from the past.

Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and aggregation of the soluble cellular prion proteins (PrPC) into scrapie isoform (PrPSc) in the Central nervous system (CNS) resulted in brain damage and other neurological symptoms. Different therapeutic approaches, including stalling PrPC to PrPSc conversion, increasing PrPSc removal, and PrPC stabilization, for which a spectrum of compounds, ranging from organic compounds to antibodies, have been explored. Additionally, a non-PrP targeted drug strategy using serpin inhibitors has been discussed. Despite numerous scaffolds being screened for anti-prion activity in vitro, only a few were effective in vivo and unfortunately, almost none of them proved effective in the clinical studies, most likely due to toxicity and lack of permeability. Recently, encouraging results from a prion-protein monoclonal antibody, PRN100, were presented in the first human trial on CJD patients, which gives a hope for better future for the discovery of other new molecules to treat prion diseases. In this comprehensive review, we have re-visited the history and discussed various classes of anti-prion agents, their structure, mode of action, and toxicity. Understanding pathogenesis would be vital for developing future treatments for prion diseases. Based on the outcomes of existing therapies, new anti-prion agents could be identified/synthesized/designed with reduced toxicity and increased bioavailability, which could probably be effective in treating prion diseases.

Mechanistic Insights into the Neuroprotective Potential of Sacred Ficus Trees.

Ficus religiosa (Bo tree or sacred fig) and Ficus benghalensis (Indian banyan) are of immense spiritual and therapeutic importance. Various parts of these trees have been investigated for their antioxidant, antimicrobial, anticonvulsant, antidiabetic, anti-inflammatory, analgesic, hepatoprotective, dermoprotective, and nephroprotective properties. Previous reviews of Ficus mostly discussed traditional usages, photochemistry, and pharmacological activities, though comprehensive reviews of the neuroprotective potential of these Ficus species extracts and/or their important phytocompounds are lacking. The interesting phytocompounds from these trees include many bengalenosides, carotenoids, flavonoids (leucopelargonidin-3-O-ß-d-glucopyranoside, leucopelargonidin-3-O-α-l-rhamnopyranoside, lupeol, cetyl behenate, and α-amyrin acetate), flavonols (kaempferol, quercetin, myricetin), leucocyanidin, phytosterols (bergapten, bergaptol, lanosterol, ß-sitosterol, stigmasterol), terpenes (α-thujene, α-pinene, ß-pinene, α-terpinene, limonene, ß-ocimene, ß-bourbonene, ß-caryophyllene, α-trans-bergamotene, α-copaene, aromadendrene, α-humulene, alloaromadendrene, germacrene, γ-cadinene, and δ-cadinene), and diverse polyphenols (tannin, wax, saponin, leucoanthocyanin), contributing significantly to their pharmacological effects, ranging from antimicrobial action to neuroprotection. This review presents extensive mechanistic insights into the neuroprotective potential, especially important phytochemicals from F. religiosa and F. benghalensis. Owing to the complex pathophysiology of neurodegenerative disorders (NDDs), the currently existing drugs merely alleviate the symptoms. Hence, bioactive compounds with potent neuroprotective effects through a multitarget approach would be of great interest in developing pharmacophores for the treatment of NDDs.

Beauty of the beast: anticholinergic tropane alkaloids in therapeutics.

Tropane alkaloids (TAs) are among the most valued chemical compounds known since pre-historic times. Poisonous plants from Solanaceae family (Hyoscyamus niger, Datura, Atropa belladonna, Scopolia lurida, Mandragora officinarum, Duboisia) and Erythroxylaceae (Erythroxylum coca) are rich sources of tropane alkaloids. These compounds possess the anticholinergic properties as they could block the neurotransmitter acetylcholine action in the central and peripheral nervous system by binding at either muscarinic and/or nicotinic receptors. Hence, they are of great clinical importance and are used as antiemetics, anesthetics, antispasmodics, bronchodilator and mydriatics. They also serve as the lead compounds to generate more effective drugs. Due to the important pharmacological action they are listed in the WHO list of essential medicines and are available in market with FDA approval. However, being anticholinergic in action, TA medication are under the suspicion of causing dementia and cognitive decline like other medications with anticholinergic action, interestingly which is incorrect. There are published reviews on chemistry, biosynthesis, pharmacology, safety concerns, biotechnological aspects of TAs but the detailed information on anticholinergic mechanism of action, clinical pharmacology, FDA approval and anticholinergic burden is lacking. Hence the present review tries to fill this lacuna by critically summarizing and discussing the above mentioned aspects.

Vinpocetine, a PDE1 modulator, regulates markers of cerebral health, inflammation, and oxidative stress in a rat model of prenatal alcohol-induced experimental attention deficit hyperactivity disorder.

Prenatal alcohol exposure (PAE) has been shown to induce symptomatology associated with attention deficit hyperactivity disorder (ADHD) by altering neurodevelopmental trajectories. Phosphodiesterase-1 (PDE1) is expressed centrally and has been used in various experimental brain conditions. We investigated the role of vinpocetine, a PDE1 inhibitor, on behavioral phenotypes and important biochemical deficits associated with a PAE rat model of ADHD. Protein markers of cerebral health (synapsin-IIa, BDNF, and pCREB), inflammation (IL-6, IL-10, and TNF-α), and oxidative stress (TBARS, GSH, and SOD) were analyzed in three brain regions (frontal cortex, striatum, and cerebellum). Hyperactivity, inattention, and anxiety introduced in the offspring due to PAE were assayed using open-field, Y-maze, and elevated plus maze, respectively. Administration of vinpocetine (10 & 20 mg/kg, p.o. [by mouth]) to PAE rat offspring for 4 weeks resulted in improvement of the behavioral profile of the animals. Additionally, levels of protein markers such as synapsin-IIa, BDNF, pCREB, IL-10, SOD, and GSH were found to be significantly increased, with a significant reduction in markers such as TNF-α, IL-6, and TBARS in selected brain regions of vinpocetine-treated animals. Vinpocetine, a selective PDE1 inhibitor, rectified behavioral phenotypes associated with ADHD, possibly by improving cerebral function, reducing brain inflammation, and reducing brain oxidative stress. This study provides preliminary analysis and suggests that the PDE1 enzyme may be an important pharmacological tool to study ADHD as a result of PAE.

Phyto-Carbazole Alkaloids from the Rutaceae Family as Potential Protective Agents against Neurodegenerative Diseases.

Plant-derived (phyto) carbazole alkaloids are an important class of compounds, presented in the family of Rutaceae (Genera Murraya, Clausena, Glycosmis, Micromelum and Zanthoxylum). Due to several significant biological activities, such as antitumor, antibacterial, antiviral, antidiabetic, anti-HIV and neuroprotective activities of the parent skeleton (3-methylcarbazole), carbazole alkaloids are recognized as an important class of potential therapeutic agents. Neurodegenerative diseases (NDs) may exhibit a vast range of conditions, affecting neurons primarily and leading ultimately to the progressive losses of normal motor and cognitive functions. The main pathophysiological indicators of NDs comprise increasing atypical protein folding, oxidative stresses, mitochondrial dysfunctions, deranged neurotransmissions and neuronal losses. Phyto-carbazole alkaloids can be investigated for exerting multitarget approaches to ameliorating NDs. This review presents a comprehensive evaluation of the available scientific literature on the neuroprotective mechanisms of phyto-carbazole alkaloids from the Rutaceae family in ameliorating NDs.

Multi-Target Approach of Murraya koenigii Leaves in Treating Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) mainly affect neurons and gradually lead to a loss of normal motor and cognitive functions. Atypical protein homeostasis-misfolding, aggregations and accumulations, oxidative stress, inflammation, and apoptosis-are common features in most NDs. To date, due to the complex etiology and pathogenesis of NDs, no defined treatment is available. There has been increasing interest in plant extracts as potential alternative medicines as the presence of various active components may exert synergistic and multi-pharmacological effects. Murraya koenigii (Rutaceae) is utilized in Ayurvedic medicine for various ailments. Pharmacological studies evidenced its potential antioxidant, anti-inflammatory, anticancer, hepatoprotective, immunomodulatory, antimicrobial, and neuroprotective activities, among others. In line with our interest in exploring natural agents for the treatment of neurodegenerative diseases, this review presents an overview of literature concerning the mechanisms of action and the safety profile of significant bioactive components present in M. koenigii leaves to support further investigations into their neuroprotective therapeutic potential.

Withanolides from Withania somnifera Ameliorate Neutrophil Infiltration in Endotoxin-Induced Peritonitis by Regulating Oxidative Stress and Inflammatory Cytokines.

Identification of novel anti-inflammatory strategies are needed to avoid the side effects associated with the currently available therapies. Use of anti-inflammatory herbal remedies is gaining attention. The purpose of the present investigation was to evaluate the pharmacological potential of the withanolide-rich root extracts of the medical plant Withania somnifera (L.) Dunal using in vivo and in vitro models of endotoxin-induced inflammation and oxidative stress. The pharmacological effects of W. somnifera root extracts were evaluated using a mouse model of endotoxin (lipopolysaccharide)-induced peritonitis and various relevant human cell lines. HPLC analysis of the W. somnifera root extracts identified the presence of various bioactive withanolides. In vivo challenge of mice with endotoxin resulted in the infiltration of various leukocytes, specifically neutrophils, along with monocytes and lymphocytes into the peritoneal cavity. Importantly, prophylactic treatment with W. somnifera inhibited the migration of neutrophils, lymphocytes, and monocytes and decreased the release of interleukin-1ß, TNF-α, and interleukin-6 cytokines into the peritoneal cavity as identified by ELISA. Liver (glutathione peroxidase, glutathione, glutathione disulfide, superoxide dismutase, malondialdehyde, myeloperoxidase) and peritoneal fluid (nitrite) biochemical analysis revealed the antioxidant profile of W. somnifera. Similarly, in human HepG2 cells, W. somnifera significantly modulated the antioxidant levels. In THP-1 cells, W. somnifera decreased the secretion of interleukin-6 and TNF-α. In HEK-Blue reporter cells, W. somnifera inhibited TNF-α-induced nuclear factor-κB/activator protein 1 transcriptional activity. Our findings suggest the pharmacological effects of root extracts of W. somnifera rich in withanolides inhibit neutrophil infiltration, oxidative hepatic damage, and cytokine secretion via modulating the nuclear factor-κB/activator protein 1 pathway.

Phytosterols: Potential Metabolic Modulators in Neurodegenerative Diseases.

Phytosterols constitute a class of natural products that are an important component of diet and have vast applications in foods, cosmetics, and herbal medicines. With many and diverse isolated structures in nature, they exhibit a broad range of biological and pharmacological activities. Among over 200 types of phytosterols, stigmasterol and ß-sitosterol were ubiquitous in many plant species, exhibiting important aspects of activities related to neurodegenerative diseases. Hence, this mini-review presented an overview of the reported studies on selected phytosterols related to neurodegenerative diseases. It covered the major phytosterols based on biosynthetic considerations, including other phytosterols with significant in vitro and in vivo biological activities.

Mechanistic Aspects of Apiaceae Family Spices in Ameliorating Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases worldwide. In an effort to search for new strategies for treating AD, natural products have become candidates of choice. Plants are a rich source of bioactive and effective compounds used in treating numerous diseases. Various plant extracts are known to display neuroprotective activities by targeting different pathophysiological pathways in association with the diseases, such as inhibiting enzymes responsible for degrading neurotransmitters, reducing oxidative stress, neuroprotection, inhibiting amyloid plaque formation, and replenishing mitochondrial function. This review presented a comprehensive evaluation of the available scientific literature (in vivo, in vitro, and in silico) on the neuroprotective mechanisms displayed by the extracts/bioactive compounds from spices belonging to the Apiaceae family in ameliorating AD.

Biotite-Calx Based Traditional Indian Medicine Sahastraputi-Abhrak-Bhasma Prophylactically Mitigates Allergic Airway Inflammation in a Mouse Model of Asthma by Amending Cytokine Responses.

PURPOSE: Asthma is a heterogeneous airway inflammatory disease with limited therapeutic options. Traditional medicine is extensively used for treating various ailments including asthma. Sahastraputi-Abhrak-Bhasma (SPAB) is a biotite-calx based Indian medicine. METHODS: We have tested for the anti-inflammatory and anti-asthmatic properties of SPAB, using a mouse model of ovalbumin-induced allergic asthma in-vivo and cell-based assays in-vitro. Histological analysis, qPCR and ELISA were performed to assess the pathology. SEM, EDX and XRD-analysis were performed to characterize the SPAB particles. RESULTS: SEM, EDX and XRD-analysis identified the presence of SPAB particle of 100 nm-~1µm diameter and contains annite-1M, aluminium silicate, kyanite, aluminium oxide, magnesium silicate, and maghemite in the samples. Ova-challenge resulted in severe inflammatory responses, airway remodelling and increased oxidative burden in lungs. Importantly, prophylactic treatment with SPAB significantly attenuated allergen induced leukocyte infiltration specifically eosinophils, lymphocytes, macrophages and neutrophils in BALF. Ova-induced mucus hypersecretion, peri-bronchial collagen deposition, inflammatory cell infiltration and bronchial epithelial thickening were significantly abrogated upon SPAB treatment. qPCR and ELISA analysis identified that allergen induced increases in IL-5, IL-13, IL-33, IFN-γ and IL-1ß cytokines mRNA in whole lungs and the levels of IL-6, IL-1ß and TNF-α proteins in BALF were significantly attenuated upon oral SPAB treatment. SPAB restored allergen induced decreases in anti-oxidant markers in lungs. In-vitro, SPAB attenuated the secretion of IL-6, and TNF-α from human bronchial epithelial cells and modestly inhibited NF-kB/AP-1 pathway in HEK cells. CONCLUSION: Taken together, our results experimentally validated the prophylactic ameliorative potential of the Indian classical medicine Sahastraputi-Abhrak-Bhasma against asthma associated airway inflammation.

Adolescent With von Willebrand Disease Type 3 Spontaneous Abdominal Hemorrhage.

An adolescent female classified as unstable with a spontaneous abdominal hemorrhage was transferred to a level 1 pediatric trauma tertiary emergency department. Pertinent medical history included von Willebrand disease type 3, menorrhagia, and obesity. Preparation before patient arrival included mobilization of multidisciplinary medical team experts in hematology, pharmacy, blood bank, radiology, and nursing who provided lifesaving interventions. The administration of factor products, blood products, interventional radiology, emergent hepatic angiography, and embolization coordination resulted in a successful outcome. After an 18-day intensive hospital course, the patient returned home close to her baseline health status.

Nucleic acid analysis on paper substrates (NAAPs): an innovative tool for Point of Care (POC) infectious disease diagnosis.

The cost-effective rapid diagnosis of infectious diseases is an essential and important factor for curing such diseases in the global public health care picture. Owing to poor infrastructure and lack of sanitation, these diseases have an extreme impact on remote and rural areas, especially in developing countries, and there are unresolved challenges. Molecular diagnosis, such as nucleic acid analysis, plays a key role in the significant treatment of numerous infectious diseases. Current molecular diagnostic assays require a sophisticated laboratory setup with expensive components. Molecular diagnosis on a microfluidic point-of-care (POC) platform is attractive to researchers for disease detection with proper prevention. Compared to various microfluidic substrate materials, paper-based POC technologies offer significant cost-effective solutions over high-cost clinical instruments to fill the gap between the needs of users and affordability. Low-cost paper-based microfluidic POC technologies provide portable and disposable diagnostic systems for multiple disease detection that may be extremely useful in remote areas. This article presents a critical review of paper-based microfluidic device technology which has become an imminent platform to adjust the current health scenario for the detection of diseases using different stages of nucleic acid analysis, such as extraction, amplification and detection of nucleic acid, with future perspectives for paper substrates.

Anatomical variations in cortical bone surface permeability: Tibia versus femur.

Cortical bone surfaces (periosteal and endosteal) exhibit differential (re)modelling response to mechanical loading. This poses a serious challenge in establishing an in silico model to predict site-specific new bone formation as a function of mechanical stimulus. In this regard, mechanical loading-induced fluid motion in lacunar-canalicular system (LCS) is assumed osteogenic. Micro-architectural properties, especially permeability regulate canalicular fluid motion within the bone. The knowledge of these properties is required to compute flow distribution. Along the same line, it is possible that cortical surfaces may experience differential fluid distribution due to anatomical variations in microarchitectural properties which may induce distinct new bone response at cortical surfaces. Nevertheless, these properties are not well reported for cortical surfaces in the literature. Accordingly, the present study aims to measure microarchitectural properties especially permeability at different anatomical locations (medial, lateral, anterior, and posterior) of periosteal and endosteal surfaces using nanoindentation. A standard poroelastic optimization technique was used to estimate permeability, shear modulus, and Poisson's ratio. The properties are also compared for two weight-bearing bones i.e. tibia and femur. Endosteal surface was found more permeable as compared to the periosteal surface. Tibial endosteal surface had shown greater permeability values at most of the anatomical locations as compared to femoral endosteal surface. The outcomes may be used to precisely predict site-specific osteogenesis in cortical bone as a function of canalicular flow distribution. This work may ultimately be beneficial in designing the loading parameters to stimulate desired new bone response for the prevention and the cure of bone loss.

Papaverine ameliorates prenatal alcohol-induced experimental attention deficit hyperactivity disorder by regulating neuronal function, inflammation, and oxidative stress.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with complex aetiology and phenotypes. Phosphodiesterase10A (PDE10A) has been shown to provide benefits in various brain conditions. We investigated the role of papaverine, a selective PDE10A inhibitor on core phenotypes in prenatal alcohol exposure (PAE) model of ADHD. In order to identify probable mechanisms involved, the effects on several protein markers of neuronal function such as, neuronal survival-BDNF, neuronal transcription factor-pCREB, brain inflammation (IL-6, IL-10, and TNF-α), and brain oxidative stress (TBARS and GSH) were studied in frontal cortex, cerebellum, and striatum. PAE resulting hyper-locomotion, inattention, and anxiety were studied by the use of open-field, y-maze, and elevated plus maze, respectively. Administration of papaverine (15/30 mg kg-1 ) to PAE group of animals resulted in amelioration of hyperactivity, inattention, and anxiety. Also, papaverine resulted in significant increase of the levels in BDNF, pCREB, IL-10, and GSH along with significant decrease of TNF-α, IL-6, and TBARS in different brain areas of PAE group. Papaverine, a selective PDE10A inhibitor rectified behavioural phenotypes associated with ADHD, possibly by altering the protein markers associated with neuronal survival, neuronal transcription factor, brain inflammation, and brain oxidative stress. Implicating PDE10A as a possible target for furthering our understanding of ADHD phenotypes.

Herbal Decoction Divya-Peedantak-Kwath Alleviates Allodynia and Hyperalgesia in Mice Model of Chemotherapy-Induced Peripheral Neuropathy via Modulation in Cytokine Response.

The widely used cancer treatment, chemotherapy, causes severe long-term neuropathic pain in 30-40% cases, the condition clinically known as chemotherapy-induced peripheral neuropathy (CIPN). Approved conventional analgesics are sometimes ineffective, while others like opioids have undesirable side effects like addiction, seizures, and respiratory malfunctioning. Tricyclic antidepressants and anticonvulsants, although exhibit anti-allodynic effects in neuropathy, also have unpleasant side effects. Thus, alternative medicines are being explored for CIPN treatment. Despite scattered reports on different extracts from different plants having potential anti-allodynic effects against CIPN, no established medicine or formulation of herbal origin exists. In this study, efficacy of an herbal decoction, formulated based on ancient medicinal principles and protocols for treating neuropathic pain, Divya-Peedantak-Kwath (DPK), has been evaluated in a paclitaxel (PTX)-induced peripheral neuropathic mouse model. We observed that DPK has prominent anti-allodynic and anti-hyperalgesic effects and acts as a nociceptive modulator for CIPN. With exhibited antioxidative effects, DPK restored the redox potential of the sciatic nerves to the normal. On histopathological evaluation, DPK prevented the PTX-induced lesions in the sciatic nerve, in a dose-dependent manner. It also prevented inflammation by modulating the levels of pro-inflammatory cytokines involved in CIPN pathogenesis. Our observations evinced that DPK can alleviate CIPN by attenuating oxidative stress and concomitant neuroinflammation through immune modulation.