Betanin combined with virgin coconut oil inhibits neuroinflammation in aluminum chloride-induced toxicity in rats by regulating NLRP3 inflammasome.

Background and aim: Activating NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is crucial in the pathogenesis of Alzheimer's disease (AD). A multimodal treatment intervention is the most feasible way to alter the course of AD progression. Hence, the current study was conducted to study the combination of betanin (BET) and virgin coconut oil (VCO) on NLRP3 regulation in aluminum chloride-induced AD in Wistar rats. Experimental procedure: BET (100,200 mg/kg) and VCO (1, 5 g/kg) alone and in combination (BET 100 mg/kg + VCO 1 g/kg and BET 200 mg/kg + VCO 5 g/kg) were given orally for 42 days. On day 21 and 42nd, the behavioral test was performed to check the animal's cognition. Acetylcholinesterase (AChE) activity, oxidative stress markers, estimation of NLRP3 and IL-1ß, and histological examinations were conducted in the hippocampus (H) and cortex (C). Results and conclusion: Treatment with BET and VCO alone or combined improved behavioral characteristics (MWM and PA p < 0.0001; EPM p = 0.5184), inhibited AChE activity (C, p = 0.0101; H, p < 0.0001), and lowered oxidative stress in the brain. Also, combination treatment restored the levels of NLRP3 (C, p = 0.0062; H, p < 0.0001) and IL1ß (C, p = 0.0005; H, p = 0.0098). The combination treatment significantly reduced the degree of neuronal degeneration, amyloid deposition, and necrosis in the brain tissue. The current study revealed that the combination strategy effectively controlled neuroinflammation via modulation of the NLRP3 inflammasome pathway, paving the way for the new treatment.

A current review on P2X7 receptor antagonist patents in the treatment of neuroinflammatory disorders: a patent review on antagonists.

Chronic inflammation is defined by an activated microglial state linked to all neurological disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (a motor neuron disease that affects the brain and spinal cord). P2X7 receptors (P2X7R) are ATP-activated ion-gated channels present on microglial surfaces. Prolonged ATP release under pathological settings results in sustained P2X7R activation, which leads to inflammasome development and cytokine release. P2X7R and its enabling roles have recently been linked to neurodegenerative diseases, making it a potential research subject. This research provides an overview of current patents for chemicals, biologics, and medicinal applications. The World Intellectual Property Organization (WIPO), European Patent Office (EPO, Espacenet), and the United States Patent and Trademark Office (USPTO) databases were searched for patents using the keywords "P2X7R and Neuroinflammation." During the study period from 2015 to 2021, 103 patents were examined. The countries that protected these innovations were the United States, PCT (Patent Cooperation Treaty states), Europe, Canada, Australia, and India. Janssen Pharmaceutica NV had the most applications, followed by Acetelion Pharmaceuticals LTD., Renovis Inc., Kelly Michael G, Kincaid Jhon, Merck Patent GMBH, H Lundbeck A/S, and many more. The P2X7R is a possible diagnostic and therapeutic target for cancer, pain disorders, and inflammation. For P2X7 R, several compounds have been discovered and are presently the subject of clinical trial investigations. This study featured patents for P2X7R antagonists, which help treat conditions including neuroinflammation.

Betanin mitigates scopolamine-induced cognitive impairment by restoring cholinergic function, boosting brain antioxidative status, and increasing BDNF level in the zebrafish model.

Betalains obtained from Beta vulgaris (family Caryophyllales) are regularly consumed as part of the regular diet with medicinal benefits due to antioxidant and anti-inflammatory properties. The objective of this article was to evaluate betanin's neuroprotective properties in a scopolamine-induced zebrafish paradigm. Betanin (BET) (50, 100, and 200 mg/L), and donepezil (10 mg/L) were delivered to zebrafish in a treatment tank once a day for 8 days, while memory impairment was produced by scopolamine (100 µM), which was given 60 min before behavioral assessments. The treatment dosages were determined based on acute toxicity studies. The existence of betacyanin and betaxanthins of BET was tested using liquid chromatography-mass spectrometry (LC-MS). The Y-maze task was used to examine the novelty and spatial memory, while the novel tank diving test was used to assess anxiety-like behavior (NTT). The activities of acetylcholinesterase (AChE) and the oxidative stress sensitivity in zebrafish brains were examined. Also, brain-derived neurotrophic factor (BDNF) level is quantified by an ELISA kit. Scopolamine-induced rises in AChE activity, memory loss, anxiety, and brain oxidant capacity were all reduced by BET. These results suggest that BET (50 and 100 mg/L) has a therapeutic ability to treat brain oxidative stress and cognitive deficits in amnesic zebrafish.

Zebrafish as a Promising Tool for Modeling Neurotoxin-Induced Alzheimer's Disease.

Drug discovery and development for Alzheimer's disease (AD) are complex and challenging due to the higher failure rate in the drug development process. The overproduction and deposition of Aß senile plaque and intracellular neurofibrillary tangle (NFT) formation are well-recognized diagnostic hallmarks of AD. Numerous transgenic models of Alzheimer's disease have restrictions on cost-effectiveness and time in the preclinical setup. Zebrafish has emerged as an excellent complementary model for neurodegenerative research due to simpler organisms with robust, clearly visible behavior forms. Glutaminergic and cholinergic pathways responsible for learning and memory are present in zebrafish and actively participate in the transmission process. Therefore, it is imperative to study neurotoxic agents' mechanisms that induce dysfunction of memory, learning, and neurons in the zebrafish. This review illustrates the in-depth molecular mechanism of several neurotoxic agents such as okadaic acid, cigarette smoke extract, and metals to produce cognitive deficits or neurodegeneration similar to mammals. These updates would determine an ideal and effective neurotoxic agent for producing AD pathophysiology in the zebrafish brain for preclinical screening.

Inhibitors of NF-κB and P2X7/NLRP3/Caspase 1 pathway in microglia: Novel therapeutic opportunities in neuroinflammation induced early-stage Alzheimer's disease.

Microglial activation is a distinguished attribute in many neurodegenerative diseases of aging. Compelling evidence suggests that neuroinflammation stimulated by microglia, the resident macrophage-like immune cells in the brain, play a contributing role in the pathogenesis of Alzheimer's disease (AD). Postmortem brain tissue of individuals with AD has credibly demonstrated that neuroinflammation is likely to be a key driver of the disease. Recently, It has been found that manipulating ß-amyloid directly is an impracticable approach for therapeutic intervention due to the failure of ß-amyloid-lowering drugs in clinical trials. Further, Current treatments relieve only symptoms and modestly improve disease condition but do not reverse or prevent disease. Therefore, Inhibition of microglia activation is effective strategies against the multifactorial and complex AD. More recently there has been a center of attention on converting microglia from this classic state to an alternate state in which the noxious effects are reduced and their phagocytic action toward Aß improved. The nuclear factor-kappa B (NF- kB) and NLRP3 inflammasome activation by P2X7/NLRP3/caspase 1 pathways are closely linked to Alzheimer's disease (AD) via neuroinflammation, therefore it could be a rational strategy to target these proteins to counteract the AD pathology. These strategies could work effectively if therapeutic intervention started at an early stage. This review highlights the potentials of drugs acting on the P2X7 receptor and its downstream protein targets for inhibition of neuroinflammation. Thus it might act as a futuristic strategy to treat Alzheimer's disease.