Involvement of NLRP3 inflammasome pathway in the protective mechanisms of ferulic acid and p-coumaric acid in LPS-induced sickness behavior and neuroinflammation in mice.

Ferulic acid (FA) and p-coumaric acid (PCA) are abundantly present in commonly consumed food and beverages. Being polyphenolic compounds, they have been explored for their antioxidant and anti-inflammatory properties. Based on our previous study, we selected these two compounds to further investigate their potential in lipopolysaccharide (LPS)-induced sickness behavior and the ensuing neuroinflammation by specifically focusing on the NLRP3 inflammasome pathway. Male Swiss albino mice were divided into nine groups (n = 6) consisting of Normal Control, LPS, fluoxetine (FLX), FA40, FA160, FA640, PCA40, PCA160, and PCA640 respectively. Each group received respective FA or PCA treatment except Normal Control and LPS, which received the vehicle, carboxymethylcellulose 0.25% w/v. All groups were challenged with LPS 1.5 mg/kg, intraperitoneally except the Normal Control group, which received saline. Behavioral assessments were performed between 1-2 h, and the whole brains were collected at 3 h post-LPS administration. LPS-induced sickness behavior was characterized by significantly reduced spontaneous activity and high immobility time. The expression of NLRP3, ASC, caspase-1 and IL-1ß was significantly increased, along with the levels of brain IL-1ß suggesting the assembly and activation of NLRP3 inflammasome pathway. Furthermore, the major cytokines involved in sickness behavior, IL-6 and TNF-α were also significantly elevated with the accompanied lipid peroxidation. The results of this study emphasize that within the employed dose ranges of both FA and PCA, both the compounds were effective at blocking the activation of the NLRP3 inflammasome pathway and thereby reducing the release of IL-1ß and the sickness behavior symptoms. There was a prominent effect on cytokine levels and lipid peroxidation as well.

Effect of chronic low-dose treatment with chitooligosaccharides on microbial dysbiosis and inflammation associated chronic ulcerative colitis in Balb/c mice.

The study aimed to investigate the potential of low dose chitooligosaccharide (COS) in ameliorating dextran sodium sulfate (DSS) induced chronic colitis by regulating microbial dysbiosis and pro-inflammatory responses. Chronic colitis was induced in BALB/c mice by DSS (4% w/v, 3 cycles of 5 days) administration. The mice were divided into four groups: vehicle, DSS, DSS + mesalamine and DSS+COS. COS and mesalamine were administered orally, daily once, from day 1 to day 30 at a dose of 20 mg/kg and 50 mg/kg respectively. The disease activity index (DAI), colon length, histopathological score, microbial composition, and pro-inflammatory cytokine expression were evaluated. COS (20 mg/kg, COSLow) administration reduced the disease activity index, and colon shortening, caused by DSS significantly. Furthermore, COSLow restored the altered microbiome in the gut and inhibited the elevated pro-inflammatory cytokines (IL-1 and IL-6) in the colon against DSS-induced chronic colitis in mice. Moreover, COSLow treatment improved the probiotic microflora thereby restoring the gut homeostasis. In conclusion, this is the first study where microbial dysbiosis and pro-inflammatory responses were modulated by chronic COSLow treatment against DSS-induced chronic colitis in Balb/c mice. Therefore, COS supplementation at a relatively low dose could be efficacious for chronic inflammatory bowel disease.

Evaluating the Role of N-Acetyl-L-Tryptophan in the Aß 1-42-Induced Neuroinflammation and Cognitive Decline in Alzheimer's Disease.

Alzheimer's disease (AD), a neurodegenerative condition previously known to affect the older population, is also now seen in younger individuals. AD is often associated with cognitive decline and neuroinflammation elevation primarily due to amyloid ß (Aß) accumulation. Multiple pathological complications in AD call for therapies with a wide range of neuroprotection. Our study aims to evaluate the effect of N-acetyl-L-tryptophan (NAT) in ameliorating the cognitive decline and neuroinflammation induced by Aß 1-42 oligomers and to determine the therapeutic concentration of NAT in the brain. We administered Aß 1-42 oligomers in rats via intracerebroventricular (i.c.v.) injection to induce AD-like conditions. The NAT-treated animals lowered the cognitive decline in the Morris water maze characterized by shorter escape latency and increased path efficiency and platform entries. Interestingly, the hippocampus and frontal cortex showed downregulation of tumor necrosis factor, interleukin-6, and substance P levels. NAT treatment also reduced acetylcholinesterase activity and total and phosphorylated nuclear factor kappa B and Tau levels. Lastly, we observed upregulation of cAMP response element-binding protein 1 (CREB1) signaling. Surprisingly, our HPLC method was not sensitive enough to detect the therapeutic levels of NAT in the brain, possibly due to NAT concentrations being below the lowest limit of quantification of our validated method. To summarize, the administration of NAT significantly lowered cognitive decline, neuroinflammatory pathways, and Tau protein and triggered the upregulation of CREB1 signaling, suggesting its neuroprotective role in AD-like conditions.

Modulatory role of vitamins A, B3, C, D, and E on skin health, immunity, microbiome, and diseases.

Disruption of the skin barrier and immunity has been associated with several skin diseases, namely atopic dermatitis (AD), psoriasis, and acne. Resident and non-resident immune cells and the barrier system of the skin are integral to innate immunity. Recent advances in understanding skin microbiota have opened the scope of further understanding the various communications between these microbiota and skin immune cells. Vitamins, being one of the important micronutrients, have been reported to exert antioxidant, anti-inflammatory, and anti-microbial effects. The immunomodulatory action of vitamins can halt the progression of skin diseases, and thus, understanding the immuno-pharmacology of these vitamins, especially for skin diseases can pave the way for their therapeutic potential. At the same time, molecular and cellular markers modulated with these vitamins and their derivatives need to be explored. The present review is focused on significant vitamins (vitamins A, B3, C, D, and E) consumed as nutritional supplements to discuss the outcomes and scope of studies related to skin immunity, health, and diseases.

Involvement of indoleamine 2, 3-dioxygenase (IDO) and brain-derived neurotrophic factor (BDNF) in the neuroprotective mechanisms of ferulic acid against depressive-like behaviour.

OBJECTIVE: Ferulic acid (FA) is a common food ingredient that is abundantly present in various routinely consumed food and beverages. Like many cinnamic acid derivatives, FA produces wide-ranging effects in a dose-dependent manner and various studies link FA consumption with reduced risk of depressive disorders. The aim of this study was to exploit the neuroprotective mechanisms of FA including indoleamine 2,3-dioxygenase (IDO), brain-derived neurotrophic factor (BDNF), and other pro-inflammatory cytokines by employing lipopolysaccharide (LPS)-induced depressive-like behaviour model. METHODS: C57BL/6J male mice were divided into 4 groups consisting of saline (SAL), LPS, FA and Imipramine (IMI). Animals were pretreated orally with FA (10 mg/kg) and IMI (10 mg/kg) for 21 days once daily and all groups except SAL were challenged with LPS (0.83 mg/kg) intraperitoneally on day 21. RESULTS: LPS administration produced a biphasic change in the behaviour of the animals where the animals lost a significant weight and express high immobility time at 24 h. Proinflammatory cytokines including, TNF-α, IL-6, IL-1ß, and IFN-γ were significantly increased along with increased lipid peroxidation and reduced BDNF. Furthermore, the increased kynurenine to tryptophan ratio was indicative of elevated IDO activity. CONCLUSION: The results of this study emphasise that low dose of FA is effective in attenuating depressive-like behaviour by modulating IDO, BDNF and reducing neuroinflammation.

Neuroprotective effects of dietary plants and phytochemicals against radiation-induced cognitive and behavioral deficits: a comprehensive review of evidence and prospects for future research.

Exposure to ionizing radiation (IR) is a common occurrence in clinical practice and incidents involving nuclear detonation or nuclear reactor accidents. IR triggers cellular events that result in oxidative stress and damage to macromolecules, rendering it harmful. While the central nervous system (CNS) was once believed to be resistant to radiation, emerging evidence suggests that even small doses of IR can adversely impact the brain. Exposure to an unsafe dose of radiation can cause increased permeability of the blood-brain barrier (BBB), neuronal apoptosis, reduced neurogenesis, impaired synaptic plasticity, and cognitive dysfunction. In recent years, the potential benefits of dietary agents and phytochemicals for mental health and radiation-induced damage have been widely investigated. Despite this, few studies have explored the protective effects of plants against radiation-induced brain damage. Here, we present a review collating evidence on the beneficial effects of dietary plants on radiation-induced brain damage based on behavioral studies. Notably, Amaranthus paniculatus, Grewia asiatica, Lycium barbarum, and phytochemicals such as vitamin E, corilagin, curcumin, resveratrol, and ursolic acid have demonstrated potential in mitigating radiation-induced damage to the CNS. Furthermore, preliminary studies have indicated that alpha-tocopherol and the micronutrient selenium have neuroprotective effects in cancer survivors previously treated with radiation to the brain. This review focuses exclusively on behavioral outcomes to assess the impact of ionizing radiation on the CNS and the effectiveness of dietary plants and phytochemicals as neuroprotective agents against radiation-induced neuronal damage.

Emphasizing the Crosstalk Between Inflammatory and Neural Signaling in Post-traumatic Stress Disorder (PTSD).

Post-traumatic stress disorder (PTSD) is a chronic incapacitating condition with recurrent experience of trauma-related memories, negative mood, altered cognition, and hypervigilance. Agglomeration of preclinical and clinical evidence in recent years specified that alterations in neural networks favor certain characteristics of PTSD. Besides the disruption of hypothalamus-pituitary-axis (HPA) axis, intensified immune status with elevated pro-inflammatory cytokines and arachidonic metabolites of COX-2 such as PGE2 creates a putative scenario in worsening the neurobehavioral facet of PTSD. This review aims to link the Diagnostic and Statistical Manual of mental disorders (DSM-V) symptomology to major neural mechanisms that are supposed to underpin the transition from acute stress reactions to the development of PTSD. Also, to demonstrate how these intertwined processes can be applied to probable early intervention strategies followed by a description of the evidence supporting the proposed mechanisms. Hence in this review, several neural network mechanisms were postulated concerning the HPA axis, COX-2, PGE2, NLRP3, and sirtuins to unravel possible complex neuroinflammatory mechanisms that are obscured in PTSD condition.

Dopaminergic Signaling as a Plausible Modulator of Astrocytic Toll-Like Receptor 4: A Crosstalk between Neuroinflammation and Cognition.

Neuroinflammation is one of the major pathological factors leading to Alzheimer's disease (AD). The role of microglial cells in neuroinflammation associated with AD has been known for a long time. Recently, astrocytic inflammatory responses have been linked to the neuronal degeneration and pathological development of AD. Lipopolysaccharide (LPS) and Amyloid Beta (Aß) activate astrocytes and microglial cells via toll-like 4 (TLR4) receptors leading to neuroinflammation. Reactive (activated) astrocytes mainly comprising of A1 astrocytes (A1s) are involved in neuroinflammation, while A2 astrocytes (A2s) possess neuroprotective activity. Studies link low dopamine (DA) levels during the early stages of neurodegenerative disorders with its anti-inflammatory and immuoregulatory properties. DA mediates neuroprotection via inhibition of the A1 astrocytic pathway through blockade of NF-kB and nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3); and promotion of A2 astrocytic pathways leading to the formation of neurotrophic factors like BDNF and GDNF. In this current review, we have discussed the crosstalk between the dopaminergic system in astrocytic TLR4 and NF-kB in addition to NLRP3 inflammasome in the modulation of neuroinflammatory pathologies in cognitive deficits.

Avanafil mediated dual inhibition of IKKß and TNFR1 in an experimental paradigm of Alzheimer's disease: in silico and in vivo approach.

In Alzheimer's disease pathology, inhibitors of nuclear factor kappa-ß kinase subunit ß (IKKB) and Tumor necrosis factor receptor 1 (TNFR1) signaling are linked to neuroinflammation-mediated cognitive decline. We explored the role of a phosphodiesterase 5 inhibitor (PDE5I) with dual antagonistic action on IKKB and TNFR1 to inhibit nuclear factor kappa B (NF-kB) and curb neuroinflammation. In the in silico approach, the FDA-approved Zinc 15 library was docked with IKKB and TNFR1. The top compound with dual antagonistic action on IKKB and TNFR1 was selected based on bonding and non-bonding interactions. Further, induced fit docking (IFD), molecular mechanics-generalized Born and surface area (MMGBSA), and molecular dynamic studies were carried out and evaluated. Lipopolysaccharide (LPS) administration caused a neuroinflammation-mediated cognitive decline in mice. Two doses of avanafil were administered for 28 days while LPS was administered for 10 days. Morris water maze (MWM) along with the passive avoidance test (PAT) were carried out. Concurrently brain levels of inflammatory markers, oxidative parameters, amyloid beta (Aß), IKKB and NF-kB levels were estimated. Avanafil produced good IKKB and TNFR1 binding ability. It interacted with crucial inhibitory amino acids of IKKB and TNFR1. MD analysis predicted good stability of avanafil with TNFR1 and IKKB. Avanafil 6 mg/kg could significantly improve performance in MWM, PAT and oxidative parameters and reduce Aß levels and inflammatory markers. As compared to avanafil 3 mg/kg, 6 mg/kg dose was found to exert better efficacy against elevated Aß , neuroinflammatory cytokines and oxidative markers while improving behavioural parameters.Communicated by Ramaswamy H. Sarma.

Nanoparticle-mediated active and passive drug targeting in oral squamous cell carcinoma: current trends and advances.

Oral squamous cell carcinoma (OSCC) is an invasive and highly malignant cancer with significant morbidity and mortality. Existing treatments including surgery, chemotherapy and radiation have poor overall survival rates and prognosis. The intended therapeutic effects of chemotherapy are limited by drug resistance, systemic toxicity and adverse effects. This review explores advances in OSCC treatment, with a focus on lipid-based platforms (solid lipid nanoparticles, nanostructured lipid carriers, lipid-polymer hybrids, cubosomes), polymeric nanoparticles, self-assembling nucleoside nanoparticles, dendrimers, magnetic nanovectors, graphene oxide nanostructures, stimuli-responsive nanoparticles, gene therapy, folic acid receptor targeting, gastrin-releasing peptide receptor targeting, fibroblast activation protein targeting, urokinase-type plasminogen activator receptor targeting, biotin receptor targeting and transferrin receptor targeting. This review also highlights oncolytic viruses as OSCC therapy candidates.

Astrocytic MicroRNAs and Transcription Factors in Alzheimer's Disease and Therapeutic Interventions.

Astrocytes are important for maintaining cholesterol metabolism, glutamate uptake, and neurotransmission. Indeed, inflammatory processes and neurodegeneration contribute to the altered morphology, gene expression, and function of astrocytes. Astrocytes, in collaboration with numerous microRNAs, regulate brain cholesterol levels as well as glutamatergic and inflammatory signaling, all of which contribute to general brain homeostasis. Neural electrical activity, synaptic plasticity processes, learning, and memory are dependent on the astrocyte-neuron crosstalk. Here, we review the involvement of astrocytic microRNAs that potentially regulate cholesterol metabolism, glutamate uptake, and inflammation in Alzheimer's disease (AD). The interaction between astrocytic microRNAs and long non-coding RNA and transcription factors specific to astrocytes also contributes to the pathogenesis of AD. Thus, astrocytic microRNAs arise as a promising target, as AD conditions are a worldwide public health problem. This review examines novel therapeutic strategies to target astrocyte dysfunction in AD, such as lipid nanodiscs, engineered G protein-coupled receptors, extracellular vesicles, and nanoparticles.

Putative involvement of sirtuin modulators in LPS-induced sickness behaviour in mice.

NAD+-dependent histone deacetylases (sirtuins 1-7) have been shown to be involved in various pathophysiological conditions including their involvement in cardiovascular, cancerous, neurodegenerative, immune dysregulation and inflammatory conditions. This study investigates the inflammomodulatory potential of resveratrol (RES), a sirtuin activator and sirtinol (SIR), a sirtuin inhibitor in lipopolysaccharide (LPS)-induced model of sickness behaviour in mice. Male Swiss albino mice were divided into five groups (n = 6) consisting of saline (SAL), LPS, RES, SIR, and fluoxetine (FLU) respectively, each group except LPS was prepared by intraperitoneally (i.p.) administration of SAL (10 mL/kg), RES (50 mg/kg), SIR (2 mg/kg) and FLU (10 mg/kg). Thirty minutes after the treatments, all the groups, except SAL were administered LPS (2 mg/kg, i.p.). The behavioural assays including, open field test, forced swim test, and tail suspension tests were conducted 1 h after LPS challenge. LPS administration significantly reduced the locomotor activity along with inducing a state of high immobility and that was prevented by pretreatment with RES and SIR. Further, various proinflammatory cytokines (TNF-α, IL-6, and IL-1ß), and oxidative stress markers (MDA and GSH) were found to be significantly elevated in the brain homogenates after LPS treatment. SIR pretreatment abrogated the LPS-induced neuroinflammatory and oxidative stress changes, whereas RES was only effective in reducing the oxidative stress and TNF-α levels. The results of this study speculate that the role of SIRT modulators in neuroinflammatory conditions could vary with their dose, regimen and chemical properties. Further studies with detailed molecular and pharmacokinetic profiling will be needed to explore their therapeutic potentials.

Astrocytic Glutamatergic Transmission and Its Implications in Neurodegenerative Disorders.

Several neurodegenerative disorders involve impaired neurotransmission, and glutamatergic neurotransmission sets a prototypical example. Glutamate is a predominant excitatory neurotransmitter where the astrocytes play a pivotal role in maintaining the extracellular levels through release and uptake mechanisms. Astrocytes modulate calcium-mediated excitability and release several neurotransmitters and neuromodulators, including glutamate, and significantly modulate neurotransmission. Accumulating evidence supports the concept of excitotoxicity caused by astrocytic glutamatergic release in pathological conditions. Thus, the current review highlights different vesicular and non-vesicular mechanisms of astrocytic glutamate release and their implication in neurodegenerative diseases. As in presynaptic neurons, the vesicular release of astrocytic glutamate is also primarily meditated by calcium-mediated exocytosis. V-ATPase is crucial in the acidification and maintenance of the gradient that facilitates the vesicular storage of glutamate. Along with these, several other components, such as cystine/glutamate antiporter, hemichannels, BEST-1, TREK-1, purinergic receptors and so forth, also contribute to glutamate release under physiological and pathological conditions. Events of hampered glutamate uptake could promote inflamed astrocytes to trigger repetitive release of glutamate. This could be favorable towards the development and worsening of neurodegenerative diseases. Therefore, across neurodegenerative diseases, we review the relations between defective glutamatergic signaling and astrocytic vesicular and non-vesicular events in glutamate homeostasis. The optimum regulation of astrocytic glutamatergic transmission could pave the way for the management of these diseases and add to their therapeutic value.

Neuroprotective effect of Mulmina Mango against chemotherapy-induced cognitive decline in mouse model of mammary carcinoma.

The post-treatment status of breast cancer survivors has become a concern because of the toxicity induced by chemotherapeutic agents in the brain tissues resulting in cognitive deficits, which is generally referred as chemobrain. The aim of this study was to assess the effect of a proprietary ayurvedic formulation Mulmina Mango against chemotherapy-induced cognitive impairment (CICI). Mammary carcinoma was induced by subcutaneously inoculating 4T1 cells into the mammary fat pad of the animals. Intraperitoneal administration of Cyclophosphamide, Methotrexate, 5-Fluorouracil (CMF) regimen was carried out once a week for three weeks. Treatment of Mulmina began one week before chemotherapy and continued till the end of the chemotherapy cycle. After three cycles of chemotherapy, cognitive decline was assessed by Morris water maze task followed by assessment of locomotor activity by open-field test. Tumor progression was evaluated by measurement of tumor volume. Oxidative and neuroinflammatory markers were also evaluated from the isolated brain samples. CMF treatment resulted in a considerable reduction in tumour volume. We found chemotherapy negatively affected behavioral and biochemical parameters in animals and Mulmina treatment ameliorated these cognitive impairments by restoring antioxidant and maintaining cytokine levels. The combination of phytochemicals in Mulmina proved its possible ability to alleviate CICI without affecting chemotherapeutic efficiency and could pave the way for identifying treatment strategies to combat chemobrain.

Reviewing the importance of TLR-NLRP3-pyroptosis pathway and mechanism of experimental NLRP3 inflammasome inhibitors.

Cells encounter continuous challenges due to tissue insult caused by endogenous and/or exogenous stimuli. Among the mechanisms set in place to counterbalance the tissue insult, innate immunity is always at the forefront. Cells of innate immunity efficiently recognize the 'danger signals' via a specialized set of membrane-bound receptors known as Toll-like receptors. Once this interaction is established, toll-like receptor passes on the responsibility to cytosolic NOD-like receptors through a cascade of signalling pathways. Subsequently, NOD-like receptors assemble to a specialized multiprotein intracellular complex, that is inflammasome. Inflammasome activates Caspase-1 and Gasdermin-D which initiate pyroptotic cell death in the affected tissue by two simultaneous mechanisms. Being a protease, caspase-1 cleaves and activates pro-inflammatory cytokines IL-1ß and IL-18. On the other hand, Gasdermin-D causes proteolytic cleavage which forms a pore in the cell membrane. This review highlights the molecular events ranging from recognition of stimuli to pyroptosis. The review is also an attempt to discuss the mechanisms of the most specific experimental NLRP3 inhibitors.

A Review on the Role of Endogenous Neurotrophins and Schwann Cells in Axonal Regeneration.

Injury to the peripheral nerve is traditionally referred to acquired nerve injury as they are the result of physical trauma due to laceration, stretch, crush and compression of nerves. However, peripheral nerve injury may not be completely limited to acquired physical trauma. Peripheral nerve injury equally implies clinical conditions like Guillain-Barré syndrome (GBS), Carpal tunnel syndrome, rheumatoid arthritis and diabetes. Physical trauma is commonly mono-neuropathic as it engages a single nerve and produces focal damage, while in the context of pathological conditions the damage is divergent involving a group of the nerve causing polyneuropathy. Damage to the peripheral nerve can cause a diverse range of manifestations from sensory impairment to loss of function with unpredictable recovery patterns. Presently no treatment option provides complete or functional recovery in nerve injury, as nerve cells are highly differentiated and inert to regeneration. However, the regenerative phenotypes in Schwann cells get expressed when a signalling cascade is triggered by neurotrophins. Neurotrophins are one of the promising biomolecules that are released naturally post-injury with the potential to exhibit better functional recovery. Pharmacological intervention modulating the expression of these neurotrophins such as brain-derived neurotrophic factor (BDNF) and pituitary adenylyl cyclase-activating peptide (PACAP) can prove to be a significant treatment option as endogenous compounds which may have remarkable innate advantage showing maximum 'biological relevance'.

Remedial effects of caffeine against depressive-like behaviour in mice by modulation of neuroinflammation and BDNF.

Objective: Caffeine (CAF) is one of the most commonly consumed nutritional stimulant in beverages. Interestingly, CAF produces varied effects in a dose-dependent manner, and that makes it one of the most controversial nutritional ingredients. Various studies have linked CAF consumption and reduced risk of depressive disorders. The aim of this study was to investigate the effect of CAF on lipopolysaccharide (LPS)-induced neuroinflammation and depressive-like behaviour.Methods: C57BL/6J male mice were divided into four groups consisting of saline (SAL), LPS, CAF and Imipramine (IMI). Animals were pretreated orally with CAF (10 mg/kg) and IMI (10 mg/kg) for 14 days once daily and all groups except SAL were challenged with LPS (0.83 mg/kg) intraperitoneally on day 14.Results: LPS produced a biphasic behavioural response with a significantly high immobility time and weight loss after 24 h. The brain cytokines (TNF-α, IL-6, IL-1ß, and IFN-γ) levels were remarkably high, along with increased lipid peroxidation and reduced Brain Derived Neurotrophic Factor (BDNF). These biochemical and behavioural changes were significantly alleviated by CAF and IMI chronic treatment.Conclusion: The results of this study implicate that mild-moderate consumption of CAF could impart anti-inflammatory properties under neuroinflammatory conditions by modulating the cytokine and neurotrophic mechanisms.

In silico screening of neurokinin receptor antagonists as a therapeutic strategy for neuroinflammation in Alzheimer's disease.

Neuroinflammation is one of the detrimental factors leading to neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative disorders. The activation of microglial neurokinin 1 receptor (NK1R) by substance P (SP) enhances neuroinflammation which is mediated through pro-inflammatory pathways involving NFkB, ERK1/2, and P38 and thus projects the scope and importance of NK1R inhibitors. Emphasizing the inhibitory role of N Acetyl L Tryptophan (L-NAT) on NK1R, this is the first in silico screening of L-NAT mediated NK1R antagonism. In addition, FDA- approved ligands were screened for their potential NK1R antagonism. The L-NAT was docked in XP (Extra Precision) mode while FDA-approved ligands were screened in HTVS (High Throughput Virtual Screening), SP (Standard Precision), and XP mode onto NK1R (PDB:6HLO). The L-NAT and top 3 compounds FDA-approved ligands were subjected to molecular dynamics (MD) studies of 100 ns simulation time. The XP docking of L-NAT, indacaterol, modafinil and alosetron showed good docking scores. Their 100 ns MD showed brief protein-ligand interactions with an acceptable root mean square deviation. The protein-ligand contacts depicted pi-pi stacking, pi-cation, hydrogen bonds, and water bridges with the amino acids necessary for NK1R inhibition. The variable colour band intensities on the protein-ligand contact map indicated their binding strength with amino acids. The molecular mechanics/generalized born surface area (MM-GBSA) scores suggested favourable binding free energy of the complexes. Thus, our study predicted the ability of L-NAT, indacaterol, modafinil, and alosetron as capable NK1R inhibitors that can aid to curb neuroinflammation in conditions of AD which could be further ascertained in subsequent studies.

Animal models of chemotherapy-induced cognitive decline in preclinical drug development.

RATIONALE: Chemotherapy-induced cognitive impairment (CICI), chemobrain, and chemofog are the common terms for mental dysfunction in a cancer patient/survivor under the influence of chemotherapeutics. CICI is manifested as short/long term memory problems and delayed mental processing, which interferes with a person's day-to-day activities. Understanding CICI mechanisms help in developing therapeutic interventions that may alleviate the disease condition. Animal models facilitate critical evaluation to elucidate the underlying mechanisms and form an integral part of verifying different treatment hypotheses and strategies. OBJECTIVES: A methodical evaluation of scientific literature is required to understand cognitive changes associated with the use of chemotherapeutic agents in different preclinical studies. This review mainly emphasizes animal models developed with various chemotherapeutic agents individually and in combination, with their proposed mechanisms contributing to the cognitive dysfunction. This review also points toward the analysis of chemobrain in healthy animals to understand the mechanism of interventions in absence of tumor and in tumor-bearing animals to mimic human cancer conditions to screen potential drug candidates against chemobrain. RESULTS: Substantial memory deficit as a result of commonly used chemotherapeutic agents was evidenced in healthy and tumor-bearing animals. Spatial and episodic cognitive impairments, alterations in neurotrophins, oxidative and inflammatory markers, and changes in long-term potentiation were commonly observed changes in different animal models irrespective of the chemotherapeutic agent. CONCLUSION: Dyscognition exists as one of the serious side effects of cancer chemotherapy. Due to differing mechanisms of chemotherapeutic agents with differing tendencies to alter behavioral and biochemical parameters, chemotherapy may present a significant risk in resulting memory impairments in healthy as well as tumor-bearing animals.

Dietary agents in mitigating chemotherapy-related cognitive impairment (chemobrain or chemofog): first review addressing the benefits, gaps, challenges and ways forward.

Chemobrain or chemofog is one of the important but less investigated side effects, where the cancer survivors treated with chemotherapy develop long-term cognitive impairments, affecting their quality of life. The biological mechanisms triggering the development of chemobrain are largely unknown. However, a literature study suggests the generation of free radicals, oxidative stress, inflammatory cytokines, epigenetic chromatin remodeling, decreased neurogenesis, secretion of brain-derived neurotropic factor (BDNF), dendritic branching, and neurotransmitter release to be the cumulative contributions to the ailment. Unfortunately, there is no means to prevent/mitigate the development and intensity of chemobrain. Given the lack of effective prevention strategies or treatments, preclinical studies have been underway to ascertain the usefulness of natural products in mitigating chemobrain in the recent past. Natural products used in diets have been shown to provide beneficial effects by inhibition of free radicals, oxidative stress, inflammatory processes, and/or concomitant upregulation of various cell survival proteins. For the first time, this review focuses on the published effects of astaxanthin, omega-3 fatty acids, ginsenoside, cotinine, resveratrol, polydatin, catechin, rutin, naringin, curcumin, dehydrozingerone, berberine, C-phycocyanin, the higher fungi Cordyceps militaris, thyme (Thymus vulgaris) and polyherbal formulation Mulmina™ in mitigating cognitive impairments in preclinical models of study, and also addresses their potential neuro-therapeutic mechanisms and applications in preventing/ameliorating chemobrain.