Intermittent fasting along with hydroalcoholic extract of Centella-asiatica ameliorates sub-acute hypoxia-induced ischemic stroke in adult zebrafish.

Reduced blood flow (hypoxia) to the brain is thought to be the main cause of strokes because it deprives the brain of oxygen and nutrients. An increasing amount of evidence indicates that the Centella-Asiatica (HA-CA) hydroalcoholic extract has a variety of pharmacological benefits, such as antioxidant activity, neuroprotection, anti-inflammatory qualities, and angiogenesis promotion. Intermittent fasting (IF) has neurological benefits such as anti-inflammatory properties, neuroprotective effects, and the ability to enhance neuroplasticity. The current study evaluates the combined effect of IF (for 1, 6, and 12 days) along with HA-CA (daily up to 12 days) in adult zebrafish subjected to hypoxia every 5 min for 12 days followed by behavioral (novel tank and open-field tank test), biochemical (SOD, GSH-Px, and LPO), inflammatory (IL-10, IL-1ß, and TNF-α), mitochondrial enzyme activities (Complex-I, II, and IV), signaling molecules (AMPK, MAPK, GSK-3ß, Nrf2), and imaging/staining (H&E, TTC, and TEM) analysis. Results show that sub-acute hypoxia promotes the behavioral alterations, and production of radical species and alters the oxidative stress status in brain tissues of zebrafish, along with mitochondrial dysfunction, neuroinflammation, and alteration of signaling molecules. Nevertheless, HA-CA along with IF significantly ameliorates these defects in adult zebrafish as compared to their effects alone. Further, imaging analysis significantly provided evidence of infarct damage along with neuronal and mitochondrial damage which was significantly ameliorated by IF and HA-CA. The use of IF and HA-CA has been proven to enhance the physiological effects of hypoxia in all dimensions.

Modeling Huntington's disease: An insight on in-vitro and in-vivo models.

Huntington's disease is a neurodegenerative illness that causes neuronal death most extensively within the basal ganglia. There is a broad class of neurologic disorders associated with the expansion of polyglutamine (polyQ) repeats in numerous proteins. Several other molecular mechanisms have also been implicated in HD pathology, including brain-derived neurotrophic factor (BDNF), mitochondrial dysfunction, and altered synaptic plasticity in central spiny neurons. HD pathogenesis and the effectiveness of therapy approaches have been better understood through the use of animal models. The pathological manifestations of the disease were reproduced by early models of glutamate analog toxicity and mitochondrial respiration inhibition. Because the treatments available for HD are quite limited, it is important to have a definite preclinical model that mimics all the aspects of the disease. It can be used to study mechanisms and validate candidate therapies. Although there hasn't been much success in translating animal research into clinical practice, each model has something special to offer in the quest for a deeper comprehension of HD's neurobehavioral foundations. This review provides insight into various in-vitro-and in-vivo models of HD which may be useful in the screening of newer therapeutics for this incapacitating disorder.

Role of Autophagy and Mitophagy in Neurodegenerative Disorders.

Autophagy is a self-destructive cellular process that removes essential metabolites and waste from inside the cell to maintain cellular health. Mitophagy is the process by which autophagy causes disruption inside mitochondria and the total removal of damaged or stressed mitochondria, hence enhancing cellular health. The mitochondria are the powerhouses of the cell, performing essential functions such as ATP (adenosine triphosphate) generation, metabolism, Ca2+ buffering, and signal transduction. Many different mechanisms, including endosomal and autophagosomal transport, bring these substrates to lysosomes for processing. Autophagy and endocytic processes each have distinct compartments, and they interact dynamically with one another to complete digestion. Since mitophagy is essential for maintaining cellular health and using genetics, cell biology, and proteomics techniques, it is necessary to understand its beginning, particularly in ubiquitin and receptor-dependent signalling in injured mitochondria. Despite their similar symptoms and emerging genetic foundations, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) have all been linked to abnormalities in autophagy and endolysosomal pathways associated with neuronal dysfunction. Mitophagy is responsible for normal mitochondrial turnover and, under certain physiological or pathological situations, may drive the elimination of faulty mitochondria. Due to their high energy requirements and post-mitotic origin, neurons are especially susceptible to autophagic and mitochondrial malfunction. This article focused on the importance of autophagy and mitophagy in neurodegenerative illnesses and how they might be used to create novel therapeutic approaches for treating a wide range of neurological disorders.

Therapeutic management of ischemic stroke.

Stroke is the third leading cause of years lost due to disability and the second-largest cause of mortality worldwide. Most occurrences of stroke are brought on by the sudden occlusion of an artery (ischemic stroke), but sometimes they are brought on by bleeding into brain tissue after a blood vessel has ruptured (hemorrhagic stroke). Alteplase is the only therapy the American Food and Drug Administration has approved for ischemic stroke under the thrombolysis category. Current views as well as relevant clinical research on the diagnosis, assessment, and management of stroke are reviewed to suggest appropriate treatment strategies. We searched PubMed and Google Scholar for the available therapeutic regimes in the past, present, and future. With the advent of endovascular therapy in 2015 and intravenous thrombolysis in 1995, the therapeutic options for ischemic stroke have expanded significantly. A novel approach such as vagus nerve stimulation could be life-changing for many stroke patients. Therapeutic hypothermia, the process of cooling the body or brain to preserve organ integrity, is one of the most potent neuroprotectants in both clinical and preclinical contexts. The rapid intervention has been linked to more favorable clinical results. This study focuses on the pathogenesis of stroke, as well as its recent advancements, future prospects, and potential therapeutic targets in stroke therapy.

Piperine loaded metal organic frameworks reverse doxorubicin induced chemobrain in adult zebrafish.

The study's primary goal was to enhance medicinal potential of piperine (PIP)-loaded zeolitic imidazolate frameworks-8 (PIP@ZIF-8) against doxorubicin (DOX)-induced cognitive impairments in zebrafish. Herein, PIP@ZIF-8 was synthesized via easy, economical and reproducible ultrasonication method followed by spray drying technology. ZIF-8's structural integrity has been confirmed by PXRD, and even after PIP was encapsulated, the structure of ZIF-8 remained unchanged. Pure ZIF-8 and PIP@ZIF-8 were subjected to TEM analysis, which revealed hexagonal morphology with a nanosize range. FTIR and UV-Visible spectroscopy studies confirmed the drug loading of ZIF-8. Studies on in vitro release revealed 71.48 ± 7.21% and 34.56 ± 5.35% PIP release from PIP@ZIF-8 and unformulated PIP, respectively in pH 7.4. The highest antioxidant scavenging results were obtained with vitamin C (73.77 ± 6.7%) at an intensity of 200 µg/ml, though it was 65.09 ± 2.5% and 57.99 ± 3.1% for PIP@ZIF-8 and PIP, respectively. In vivo studies on zebrafish showed that DOX administration remarkably impaired cognitive activity in T-Maze, and downregulated spatial memory and locomotor activity in the open field test. In addition, DOX administration caused a downregulation in GSH and SOD levels and increase in LPO, AChE and TNF-α levels compared to the vehicle group along with changes in brain histopathology. Further, PIP@ZIF-8 reversed the DOX-induced cognitive impairments by its antioxidant and neuroprotective properties. It can be concluded that PIP@ZIF-8 has a promising therapeutic potential against the chemotherapy-induced cognitive impairments in zebrafish.

The Role of Mitophagy in Various Neurological Diseases as a Therapeutic Approach.

Mitochondria are critical to multiple cellular processes, from the production of adenosine triphosphate (ATP), maintenance of calcium homeostasis, synthesis of key metabolites, and production of reactive oxygen species (ROS) to maintain necrosis, apoptosis, and autophagy. Therefore, proper clearance and regulation are essential to maintain various physiological processes carried out by the cellular mechanism, including mitophagy and autophagy, by breaking down the damaged intracellular connections under the influence of various genes and proteins and protecting against various neurodegenerative diseases such as Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), and Huntington disease (HD). In this review, we will discuss the role of autophagy, selective macroautophagy, or mitophagy, and its role in neurodegenerative diseases along with normal physiology. In addition, this review will provide a better understanding of the pathways involved in neuron autophagy and mitophagy and how mutations affect these pathways in the various genes involved in neurodegenerative diseases. Various new findings indicate that the pathways that remove dysfunctional mitochondria are impaired in these diseases, leading to the deposition of damaged mitochondria. Apart from that, we have also discussed the therapeutic strategies targeting autophagy and mitophagy in neurodegenerative diseases. The mitophagy cycle results in the degradation of damaged mitochondria and the biogenesis of new healthy mitochondria, also highlighting different stages at which a particular neurodegenerative disease could occur.

Quercetin ameliorates lipopolysaccharide-induced neuroinflammation and oxidative stress in adult zebrafish.

BACKGROUND: Quercetin is a natural flavonoid that is known to have numerous pharmacological activities such as antioxidative, anti-inflammatory, and neuroprotective effects against various neurological disorders. Lipopolysaccharide (LPS) is a potent endotoxin, reported causing several neurological disorders. AIM: The present study was designed to investigate the possibility that quercetin ameliorates LPS induced oxidative stress and neuroinflammation in adult zebrafish. MATERIALS AND METHODS: Zebrafish (weighing 470-530 mg) were treated with a single injection of LPS (1 mg/kg) intraperitoneally (i.p.) followed by post-treatment with quercetin (50 and 100 mg/kg; i.p.) for 7 days. After sacrificing brain was harvested and subjected for biochemical, molecular, and histological analyses. RESULTS: Results revealed post-treatment with quercetin was able to ameliorate the behavioral abnormalities as in novel tank diving test- time spent in the top zone (TSTZ), and the number of entries in the top zone was significantly (p < 0.01) more as compared to time spent in the bottom zone (TSBZ). In the light-dark chamber test- time spent in the light zone (TSLZ), and the number of entries in the light zone were significantly (p < 0.01) more as compared to time spent in the dark compartment (TSDC). Additionally, results of histopathology (H & E stain) studies showed less disruption in neuronal cells as compared to the LPS treated group. Moreover, the results of the molecular analysis revealed that quercetin treatment significantly (p < 0.01) decrease TNF-α and IL-1ß levels as compared to LPS treated animals. Further, results of the biochemical analysis reveal that quercetin significantly (p < 0.01) reduces the level of LPO, nitrite, AChEs and increases anti-oxidant GSH. CONCLUSION: Quercetin treatment helps to prevent oxidative damage and neuroinflammation in LPS treated adult zebrafish.