An insight into the concept of neuroinflammation and neurodegeneration in Alzheimer's disease: targeting molecular approach Nrf2, NF-κB, and CREB.

Alzheimer's disease (AD) is a most prevalent neurologic disorder characterized by cognitive dysfunction, amyloid-ß (Aß) protein accumulation, and excessive neuroinflammation. It affects various life tasks and reduces thinking, memory, capability, reasoning and orientation ability, decision, and language. The major parts responsible for these abnormalities are the cerebral cortex, amygdala, and hippocampus. Excessive inflammatory markers release, and microglial activation affect post-synaptic neurotransmission. Various mechanisms of AD pathogenesis have been explored, but still, there is a need to debate the role of NF-κB, Nrf2, inflammatory markers, CREB signaling, etc. In this review, we have briefly discussed the signaling mechanisms and function of the NF-ĸB signaling pathway, inflammatory mediators, microglia activation, and alteration of autophagy. NF-κB inhibition is a current strategy to counter neuroinflammation and neurodegeneration in the brain of individuals with AD. In clinical trials, numbers of NF-κB modulators are being examined. Recent reports revealed that molecular and cellular pathways initiate complex pathological competencies that cause AD. Moreover, this review will provide extensive knowledge of the cAMP response element binding protein (CREB) and how these nuclear proteins affect neuronal plasticity.

Neuroprotective potential of Betulinic acid against TIO2NP induced neurotoxicity in zebrafish.

Betulinic acid (BA) is a natural triterpenoid extracted from Bacopa monnieri. BA has been reported to be used as a neuroprotective agent, but their molecular mechanisms are still unknown. Therefore, in this study, we attempted to investigate the precise mechanism of BA for its protective effect against Titanium dioxide nanoparticles (TiO2NP) induced neurotoxicity in zebrafish. Hence, our study observation showed that 10 µg/ml dose of TiO2NP caused a rigorous behavioral deficit in zebrafish. Further, biochemical analysis revealed TiO2NP significantly decreased GSH, and SOD, and increased MDA, AChE, TNF-α, IL-1ß, and IL-6 levels, suggesting it triggers oxidative stress and neuroinflammation. However, BA at doses of 2.5,5,10 mg/kg improved behavioral as well as biochemical changes in zebrafish brain. Moreover, BA also significantly raised the levels of DA, NE, 5-HT, and GABA and decreased glutamate levels in TiO2NP-treated zebrafish brain. Our histopathological analysis proved that TiO2NP causes morphological changes in the brain. These changes were expressed by increasing pyknotic neurons, which were dose-dependently reduced by Betulinic acid. Likewise, BA upregulated the levels of NRF-2 and HO-1, which can reduce oxidative stress and neuroinflammation. Thus, our study provides evidence for the molecular mechanism behind the neuroprotective effect of Betulinic acid. Rendering to the findings, we can consider BA as a suitable applicant for the treatment of AD-like symptoms.

Novel therapeutic targets for reperfusion injury in ischemic stroke: Understanding the role of mitochondria, excitotoxicity and ferroptosis.

Ischemic reperfusion injury (IRI) remains a significant challenge in various clinical settings, including stroke. Despite advances in reperfusion strategies, the restoration of blood flow to ischemic tissues often exacerbates tissue damage through a complex cascade of cellular and molecular events. In recent years, there has been growing interest in identifying novel therapeutic targets to ameliorate the detrimental effects of IRI and improve patient outcomes. This review critically evaluates emerging therapeutic targets and strategies for IRI management, such as R-spondin 3, neurolysin, glial cell gene therapy and inter alpha inhibitors. Diverse pathophysiology involved in IRI stroke such as oxidative stress, inflammation, mitochondrial dysfunction, and ferroptosis are also closely discussed. Additionally, we explored the intricate interplay between inflammation and IRI, focusing on cell-mediated gene therapy approaches and anti-inflammatory agents that hold promise for attenuating tissue damage. Moreover, we delve into novel strategies aimed at preserving endothelial function, promoting tissue repair, and enhancing cellular resilience to ischemic insults. Finally, we discuss challenges, future directions, and translational opportunities for the development of effective therapies targeting ischemic reperfusion injury.

Neurological Manifestations Following Traumatic Brain Injury: Role of Behavioral, Neuroinflammation, Excitotoxicity, Nrf-2 and Nitric Oxide.

Traumatic Brain Injury (TBI) is attributed to a forceful impact on the brain caused by sharp, penetrating bodies, like bullets and any sharp object. Some popular instances like falls, traffic accidents, physical assaults, and athletic injuries frequently cause TBI. TBI is the primary cause of both mortality and disability among young children and adults. Several individuals experience psychiatric problems, including cognitive dysfunction, depression, post-traumatic stress disorder, and anxiety, after primary injury. Behavioral changes post TBI include cognitive deficits and emotional instability (anxiety, depression, and post-traumatic stress disorder). These alterations are linked to neuroinflammatory processes. On the other hand, the direct impact mitigates inflammation insult by the release of pro-inflammatory cytokines, namely IL-1ß, IL-6, and TNF-α, exacerbating neuronal injury and contributing to neurodegeneration. During the excitotoxic phase, activation of glutamate subunits like NMDA enhances the influx of Ca2+ and leads to mitochondrial metabolic impairment and calpain-mediated cytoskeletal disassembly. TBI pathological insult is also linked to transcriptional response suppression Nrf-2, which plays a critical role against TBI-induced oxidative stress. Activation of NRF-2 enhances the expression of anti-oxidant enzymes, providing neuroprotection. A possible explanation for the elevated levels of NO is that the stimulation of NMDA receptors by glutamate leads to the influx of calcium in the postsynaptic region, activating NOS's constitutive isoforms.

Neuroprotective potential of solanesol against tramadol induced zebrafish model of Parkinson's disease: insights from neurobehavioral, molecular, and neurochemical evidence.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and subsequent depletion of dopamine in the striatum. Solanesol, an alcohol that acts as a precursor to coenzyme Q10, possesses potential applications in managing neurological disorders with antioxidant, anti-inflammatory, and neuromodulatory potential. In this study, a zebrafish model was employed to investigate the effects of solanesol in tramadol induced PD like symptoms. Zebrafish were administered tramadol injections (50 mg/kg) over a 20-day period. Solanesol was administered at doses of 25, 50, and 100 mg/kg, three hours prior to tramadol administration from day 11 to day 20. Behavioral tests assessing motor coordination were conducted on a weekly basis using open field and novel diving tank apparatus. On day 21, the zebrafish were euthanized, and brain tissues were examined for markers of oxidative stress, inflammation, and neurotransmitters level. Chronic tramadol treatment resulted in motor impairment, reduced antioxidant enzyme levels, enhanced release of proinflammatory cytokines in the striatum, and disrupted neurotransmitter balance. However, solanesol administration mitigated these effects and exhibited a neuroprotective effect against neurodegenerative alterations in the zebrafish model of PD. This was evident through improvements in behavior, modulation of biochemical markers, attenuation of neuroinflammation, restoration of neurotransmitters level, and enhancement of mitochondrial activity. The histopathological study also confirmed that solanesol dose dependently restored neuronal cell density which confirmed its neuroprotective potential. Further investigations are required to elucidate the underlying mechanisms of solanesol neuroprotective effects and evaluate its efficacy in human patients.

Neuroprotective effects: Solanesol has shown significant neuroprotective effects in a zebrafish model of Parkinson's disease induced by chronic tramadol usage.Improved behavioral performance: Administration of solanesol resulted in improved motor coordination in the open field test (OFT) and novel diving apparatus in the tramadol-induced zebrafish model of PD.Decreased inflammation: Solanesol treatment significantly reduced pro-inflammatory cytokine levels in the tramadol-induced zebrafish model of PD, indicating its anti-inflammatory properties.Restored oxidative parameters: Solanesol administration restored oxidative stress parameters, as well as catecholamine and neurotransmitter levels in the tramadol-induced zebrafish model of PD.Histopathological improvement: Solanesol administration prevented histopathological alterations induced by tramadol, indicating its ability to protect against neuronal damage in the zebrafish model of PD.

Protective effects of Embelin in Benzo[α]pyrene induced cognitive and memory impairment in experimental model of mice.

Alzheimer's disease (AD) is a neurodegenerative disease that affects the neurons in the hippocampus, resulting in cognitive and memory impairment. The most prominent clinical characteristics of AD are the production of amyloid-beta (Aß) plaques, neurofibrillary tangles, and neuroinflammation in neurons. It has been proven that embelin (Emb) possesses antioxidant, anti-inflammatory, and neuroprotective properties. Therefore, we assessed the therapeutic potential of Emb in Benzo [α]pyrene (BaP)-induced cognitive impairment in experimental mice. BaP (5 mg/kg, i. p) was given to mice daily for 28 days, and Emb (2.5, 5, and 10 mg/kg, i. p) was given from 14 to 28 days of a protocol. In addition, locomotor activity was evaluated using open-field and spatial working, and non-spatial memory was evaluated using novel object recognition tasks (NORT), Morris water maze (MWM), and Y- maze. At the end of the study, the animal tissue homogenate was used to check biochemicals, neuroinflammation, and neurotransmitter changes. BaP-treated mice showed a significant decline in locomotor activity, learning and memory deficits and augmented oxidative stress (lipid peroxidation, nitrite, and GSH). Further, BaP promoted the release of inflammatory tissue markers, decreased acetylcholine, dopamine, GABA, serotonin, and norepinephrine, and increased glutamate concentration. However, treatment with Emb at dose-dependently prevented biochemical changes, improved antioxidant levels, reduced neuroinflammation, restored neurotransmitter concentration, and inhibited the NF-κB pathway. The current study's finding suggested that Emb improved cognitive functions through antioxidant, anti-inflammatory, and neuroprotective mechanisms and inhibition of acetylcholinesterase (AChE) enzyme activities and Aß-42 accumulation.

Antidiabetic Evaluation of Kigelia pinnata Root Bark Extract in Streptozotocin-Induced Type-2 Diabetes Model of Rats.

Diabetes mellitus (DM) is the most common endocrine disorder characterized by increased blood glucose levels resulting from defective insulin secretion, resistance to insulin action, or both. DM is often associated with severe complications, and there is an increasing appreciation that cognitive function declines in DM. The aim of this research work was to evaluate Kigelia pinnata root bark extract in Streptozotocin (STZ)-induced type-2 diabetes. Experimental diabetes was induced by a single administration of STZ (60 mg/kg, intraperitoneal [i.p.]), immediately after the STZ administration, and all animals were fed with normal food and water. Nicotinamide was administered (120 mg/kg, i.p.) 15 min before STZ. The development of hyperglycemia was confirmed by the elevated blood glucose levels determined at fixed intervals, which was confirmed by measuring fasting blood glucose levels in rats' blood taken from the tail vein. Supplementation with ethanolic extract of K. pinnata root bark (EEKP) significantly reduced the elevated blood glucose in STZ-induced hyperglycemia in rats. EEKP significantly restored the biochemical and antioxidant defense system. On the final day of the protocol, the extract also reduced inflammatory cytokines in the blood serum.

Potential Therapeutic Approach using Aromatic l-amino Acid Decarboxylase and Glial-derived Neurotrophic Factor Therapy Targeting Putamen in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative illness characterized by specific loss of dopaminergic neurons, resulting in impaired motor movement. Its prevalence is twice as compared to the previous 25 years and affects more than 10 million individuals. Lack of treatment still uses levodopa and other options as disease management measures. Treatment shifts to gene therapy (GT), which utilizes direct delivery of specific genes at the targeted area. Therefore, the use of aromatic L-amino acid decarboxylase (AADC) and glial-derived neurotrophic factor (GDNF) therapy achieves an effective control to treat PD. Patients diagnosed with PD may experience improved therapeutic outcomes by reducing the frequency of drug administration while utilizing provasin and AADC as dopaminergic protective therapy. Enhancing the enzymatic activity of tyrosine hydroxylase (TH), glucocorticoid hormone (GCH), and AADC in the striatum would be useful for external L-DOPA to restore the dopamine (DA) level. Increased expression of glutamic acid decarboxylase (GAD) in the subthalamic nucleus (STN) may also be beneficial in PD. Targeting GDNF therapy specifically to the putaminal region is clinically sound and beneficial in protecting the dopaminergic neurons. Furthermore, preclinical and clinical studies supported the role of GDNF in exhibiting its neuroprotective effect in neurological disorders. Another Ret receptor, which belongs to the tyrosine kinase family, is expressed in dopaminergic neurons and sounds to play a vital role in inhibiting the advancement of PD. GDNF binding on those receptors results in the formation of a receptor-ligand complex. On the other hand, venous delivery of recombinant GDNF by liposome-based and encapsulated cellular approaches enables the secure and effective distribution of neurotrophic factors into the putamen and parenchyma. The current review emphasized the rate of GT target GDNF and AADC therapy, along with the corresponding empirical evidence.

Fucoxanthin mitigates valproic acid-induced autistic behavior through modulation of the AKT/GSK-3ß signaling pathway.

This study aimed to investigate the effects of fucoxanthin, a natural compound found in seaweed, on various aspects of autism using a rat model induced by valproic acid (VPA). Pregnant rats were administered VPA (600 mg/kg) on gestational day 12.5, and male pups were orally administered fucoxanthin at 50, 100, or 200 mg/kg beginning on post-natal day (PND) 23-43. Behavioral assessments were conducted on PND 45-53, and on PND 54, the animals were sacrificed for further biochemical analyses (superoxide dismutase (SOD) and glutathione (GSH), nitric oxide (NO)) via UV spectroscopy. Inflammatory markers (IL-17, TNF-α, and IL-1ß) were also analyzed by sandwich ELISA, and the molecular parameters were evaluated through ELISA. The results revealed that, compared with VPA, fucoxanthin improved behavior and neuronal morphology. Specifically, fucoxanthin administration was found to enhance spatial memory, reduce pain sensitivity, and improve social interaction, locomotor activity, balance, and motor coordination. Fucoxanthin also exhibited anti-inflammatory and antioxidant effects, as indicated by the restoration of SOD and GSH levels and reduced inflammatory cytokine levels. Molecular analyses revealed that fucoxanthin restored the levels of GSK-3ß and AKT. Furthermore, fucoxanthin regulates neurotransmitters, which are related to increasing GABA and reducing glutamate levels in the cortex and cerebellum. The therapeutic effects were dose-dependent, with higher doses (200 mg/kg) showing greater efficacy than lower doses (100 mg/kg) in improving behavioral, biochemical, neurotransmitter, and molecular parameters. Fucoxanthin is a potential treatment for autism, but further research, including clinical trials, is necessary to determine its effectiveness in humans.

Neuroprotective effects of Embelin in an ethidium bromide-induced multiple sclerosis in rats: Modulation of p38 MAPK signaling pathway.

BACKGROUND: Multiple sclerosis (MS) is a debilitating inflammatory disease characterized by demyelination, varied remyelination conservation, and partial axonal retention in central nervous system (CNS) lesions. The p38 mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathophysiology of MS. Embelin (EMB), derived from the Embelia ribes plant, possesses diverse biological activities, including anti-inflammatory properties. OBJECTIVE: This study aimed to investigate the neuroprotective effects of EMB in an ethidium bromide (EB)-induced model of MS in Wistar rats. METHODS: Wistar rats were randomly divided into five groups (n = 8). MS-like manifestations were induced by injecting EB (0.1 %/10 µl) into the intracerebropeduncle (ICP) region of the rat brain for seven consecutive days. EMB was administered at doses of 1.25, 2.5, and 5 mg/kg. Behavioral assessments, neuroinflammatory cytokine analysis like tumor necrosis factor-α, interleukin-1-ß, interleukin-6 (TNF-α, IL-1ß, IL-6), oxidative stress marker measurements malondialdehyde, reduced glutathione, superoxide dismutase (MDA, GSH, SOD), and nitrite (NO), Acetylcholinesterase enzyme (AchE), and neurotransmitter level analysis, dopamine, serotonin, and norepinephrine (DA, 5-HT, and NE) were conducted. RESULTS: The study assessed behavioral, neurochemical, biochemical, and neuroinflammatory parameters, along with the modulation of p38 MAPK signaling. EMB administration significantly ameliorated neurological consequences induced by EB, improving motor coordination and gait abnormalities in rats. Furthermore, EMB effectively reduced neuroinflammatory cytokines (TNF-α, IL-1ß, IL-6) and oxidative stress markers (AchE, SOD, MDA, GSH, nitrite). Notably, EMB exhibited a modulatory effect on neurotransmitter levels, increasing GABA, DA, and 5-HT, while reducing glutamate in EB-treated groups. CONCLUSION: This study demonstrates the neuroprotective potential of EMB against the EB-induced model of MS in rats. EMB administration mitigated neurological impairments, attenuated neuroinflammation, alleviated oxidative stress, and restored neurotransmitter balance. These findings highlight the promise of EMB as a therapeutic candidate for MS treatment, providing insights into its potential mechanism of action involving the modulation of p38 MAPK signaling.

GABA-transaminase: A Key Player and Potential Therapeutic Target for Neurological Disorders.

Neurological disorders such as epilepsy, autism, Huntington's disease, multiple sclerosis, and Alzheimer's disease alter brain functions like cognition, mood, movements, and language, severely compromising the well-being of persons, suffering from their negative effects. The neurotransmitters (GABA, glutamate, norepinephrine, dopamine) are found to be involved in neuronal signaling and neurotransmission. GABA, a "commanding neurotransmitter" is directly or indirectly associated with various neurological disorders. GABA is metabolized to succinic semialdehyde by a mitochondrial gamma-aminobutyric acid-transaminase (GABA-T) enzyme. Therefore, the alterations in the GABA performance in the distinct regions of the brain via GABA-T overstimulation or inhibition would play a vital role in the pathogenesis of various neurological disorders. This review emphasizes the leading participation of GABA-T in neurological disorders like Huntington's disease, epilepsy, autism, Alzheimer's disease, and multiple sclerosis. In Huntington's disease, epilepsy, and multiple sclerosis, the surfeited performance of GABA-T results in diminished levels of GABA, whereas in autism, the subsidence of GABA-T activity causes the elevation in GABA contents, which is responsible for behavioral changes in these disorders. Therefore, GABA-T inhibitors (in Huntington's disease, epilepsy, and multiple sclerosis) or agonists (in autism) can be used therapeutically. In the context of Alzheimer's disease, some researchers favor the stimulation of GABA-T activity whereas some disagree with it. Therefore, the activity of GABA-T concerning Alzheimer's disease is still unclear. In this way, studies of GABA-T enzymatic activity in contrast to neurological disorders could be undertaken to understand and be considered a therapeutic target for several GABA-ergic CNS diseases.

QbD-assisted optimisation of liposomes in chitosan gel for dermal delivery of aceclofenac as synergistic approach to combat pain and inflammation.

Aceclofenac (ACE) is a drug that was precisely devised to circumvent the shortcomings associated with diclofenac. However, ACE too corresponds to nonsteroidal anti-inflammatory drug (NSAID)-related adverse effects, but with a lower amplitude. The present investigation seeks to develop liposomes loaded with ACE adopting a central composite design (CCD) and formulate a chitosan-based hydrogel for synergistic anti-inflammatory efficacy and improved ACE dermal administration. On the basis of preliminary vesicle size, Poly Dispersity Index (PDI), and drug entrapment, the composition of lipid, cholesterol, and vitamin E TPGS were chosen as independent variables. The formulation composition met the specifications for an optimum liposomal formulation, with total lipid concentration (13.5% w/w), cholesterol concentration (10% w/w), and surfactant concentration (2% w/w). With particle size and PDI of 174.22 ± 5.46 nm and 0.285 ± 0.01 respectively, the optimised formulation achieved an entrapment effectiveness of 92.08 ± 3.56%. Based on the CCD design, the optimised formulation Acec-Lipo opt was chosen and was subsequently transformed to a chitosan-based gel formulation for in vitro drug release, penetration through the skin, in vivo analgesic therapeutic activity, and skin irritation testing. % age oedema inhibition was found to be greatest with the Acec-Lipo opt gel formulation, followed by Acec gel. These results reinforce the notion that the inclusion of chitosan resulted in a synergistic effect despite the same strength of the drug. The findings suggested that Acec-Lipo incorporated in chitosan gel for skin targeting might be an effective formulation for topical ACE administration in clinical subjects.

Apigenin protects melanocytes and improve tyrosinase activity in a hydroquinone induced vitiligo mouse model targeting P38 MAP kinase signaling: histopathology and immunohistochemistry analysis.

Apigenin (APG) is a plant-based flavonoid that possesses antioxidants, anti-inflammatory, and modulates P38 MAPK as well as tyrosinase. Hydroquinone (HQ), a phenolic compound was used to induce vitiligo in C57BL/6 mice. The present study was performed to check the therapeutic potential of apigenin in HQ-induced vitiligo via targeting P38 MAPK pathway. In the present study, 41 C57BL/6 mice were divided into six groups containing seven animals per group except normal group. (I) normal group, (II) HQ group, (III) to (IV) APG with (1%, 2.5%, 5%), and (VI) tacrolimus (TAC) group. Topical application of HQ was performed from day 1 to day 20 to, (II), (III) to (IV) APG with (1%, 2.5%, 5%), (VI) tacrolimus (TAC) group, and then APG; tacrolimus (TAC) was applied from day 21 to day 60 after removing the hair. In the case of (I) normal group and (II) HQ group, we smeared them with water for 60 days and HQ for 20 days in their individual group. On day 61 after anesthesia, a part of the target skin was peeled and blood serum was taken to check the level of malondialdehyde, cholinesterase, catalase, tyrosinase, pro-inflammatory cytokines, and expression of P38 MAPK, histology of melanin containing hair follicles and depigmentation evaluation. Applying HQ topically had a noticeable impact on depigmentation, inflammatory indicators, oxidative stress, and lowered tyrosinase activity. Further HQ reduced melanin containing hair follicles and increased expression of P38 MAPK was confirmed by histopathology and immunohistochemistry. Furthermore, application of APG and TAC after day 21 to 60 significantly reduced depigmentation, inflammatory markers, oxidative stress, and increased tyrosinase. Furthermore, APG increased melanin containing hair follicles and decreased expression of non-phosphorylated P38 MAPK, as confirmed by histopathology and immunohistochemistry. Our finding demonstrated that APG significantly prevented HQ-induced vitiligo by acting as an anti-inflammatory, increasing tyrosine, and reducing the expression of non-phosphorylated P38 MAPK.

Experimental and numerical analyses of alternate materials for performance enhancement of Jaipur foot.

BACKGROUND: The Jaipur foot is the gold standard in low-cost prosthetics, and the amputee population in low-income and middle-income countries has benefited immensely from this innovation. The ability of the Jaipur foot to mimic the behavior of a regular foot, albeit to a limited extent, has made it a popular choice among clinicians and patients. However, the immense popularity has also hindered further research because minimal efforts have been made to investigate the scope of improvement of the Jaipur foot, particularly with new materials. OBJECTIVE: This article focuses on numerical and experimental analyses of various materials for the performance enhancements of the Jaipur foot. METHODS: Contemporary materials are used in finite element analysis to filter the most suitable alternate material for microcellular rubber. The performance of the Jaipur foot fabricated with alternate material is compared with the conventional Jaipur foot through compression testing simulating gait cycle conditions. RESULTS: The EVA foot showed 1-3 mm higher deformation than the MCR foot during the dorsiflexion or heel strike phases, which indicates an appropriate shock absorption and energy storage capacity in heel striking conditions. In forefoot strike phase or plantarflexion, the EVA foot and MCR foot showed identical behavior in deformations. Replacing the MCR with EVA also resulted in reduced weight of the Jaipur foot by 23%. CONCLUSIONS: The weight reduction can help the amputee to expend less energy, thereby improving patient comfort and walking patterns and hence a more natural performance similar to a regular human foot.

Integrated fragment-based drug design and virtual screening techniques for exploring the antidiabetic potential of thiazolidine-2,4-diones: Design, synthesis and in vivo studies.

Diabetes mellitus is a metabolic disorder characterized by elevated blood sugar levels and related complications. This study focuses on harnessing and integrating fragment-based drug design and virtual screening techniques to explore the antidiabetic potential of newly synthesized thiazolidine-2,4-dione derivatives. The research involves the design of novel variations of thiazolidine-2,4-dione compounds by Fragment-Based Drug Design. The screening process involves pharmacophore based virtual screening through docking algorithms, and the identification of newly twelve top-scoring compounds. The molecular docking analysis revealed that compounds SP4e, SP4f showed highest docking scores of -9.082 and -10.345. The binding free energies of the compounds SP4e, SP4f and pioglitazone was found to be -19.9, -16.1 and -13 respectively, calculated using the Prime MM/GBSA approach. The molecular dynamic study validates the docking results. Furthermore, In the Swiss albino mice model, both SP4e and SP4f exhibited significant hypoglycaemic effects, comparable to the reference drug pioglitazone. Furthermore, these compounds demonstrated favorable effects on the lipid profile, reducing total cholesterol, triglycerides, and LDL levels while increasing HDL levels. In mice tissue, the disease control group showed PPAR-γ expression of 4.200 ± 0.24, while compound SP4f displayed higher activation at 7.84 ± 0.431 compared to compound SP4e with an activation of 7.68 ± 0.65. In zebrafish model, SP4e and SP4f showed significant reductions in blood glucose levels and lipid peroxidation, along with increased glutathione levels and catalase activity. These findings highlighted the potential of SP4e and SP4f as antidiabetic agents, warranting further exploration for therapeutic applications. The in vitro study was performed in HEK-2 cell line, the pioglitazone group demonstrated PPAR-γ expression of EC50 = 575.2, while compound SP4f exhibited enhanced activation at EC50 = 739.0 in contrast to compound SP4e activation of EC50 = 826.7.

Cladribine induces apoptosis, neuroinflammation, mitochondrial oxidative stress, tau phosphorylation and Aß (1-42) pathway in the hippocampus: An in vivo approach.

Cladribine is a purine nucleoside found to enhance toxic amyloid protein and cause memory impairment. Patients following chemotherapy treatment commonly suffer from cognitive deficits more prevalent in the elderly than adults. A previous research study revealed that cladribine has a high affinity to the brain, increases the level of amyloid precursor protein, and results in learning deficits. The study was designed to validate an animal model of cladribine administration to rats through mitochondrial oxidative stress, inflammation, apoptosis, tau phosphorylation, and amyloid-ß (1-42) accumulation. In this study, all rats were orally given cladribine (0.5 and 1 mg/kg) for 28 days, resulting in impaired spatial memory confirmed by behavioural activity. On day 29, all rats were euthanized, and the hippocampal tissues were isolated and used for the estimation of neuroinflammatory markers, biochemicals parameters (glutathione, catalase, lipid peroxidation, and nitrite), amyloid-ß (1-42) level, neurotransmitters, and nuclear factor kappa B analysis. Cladribine administration significantly elevated cytokines release, dysbalanced neurotransmitter concentration, and promoted the Aß accumulation and hyperphosphorylation of tau protein. Our study outcome confirmed that cladribine produces cognitive impairment via activation of Nuclear factor kappa B, mitochondrial oxidative stress and dysbalanced of the endogenous antioxidant defence system.

Role of Nrf2 in Oxidative Stress, Neuroinflammation and Autophagy in Alzheimer's Disease: Regulation of Nrf2 by Different Signaling Pathways.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and the leading cause of dementia. AD is characterized by the aggregation of amyloid-ß (Aß) peptide, increased levels of tau protein, and loss of redox homeostasis responsible for mitochondrial dysfunction, oxidative stress, and neuroinflammation. Excessive accumulation of toxic Aß plaques activates microglia, which initiates neuroinflammation and consequently accelerates synaptic damage and neuronal loss. Various proinflammatory cytokines release, microglia proliferation, reactive astrocyte, and oxidative (reactive oxygen species (ROS) production, level of antioxidant enzymes, redox homeostasis, and lipid peroxidation) stress play a major role in AD. Several studies revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) regulates redox homeostasis and works as an anti-inflammatory in various neurodegenerative disorders. D-Glutamate expression of transcription factor Nrf2 and its genes (glutamate-cysteine ligase catalytic subunit (GCLC), Heme oxygenase-1 (HO-1), and NADPH quinone oxidoreductase I (NQO1)) has been found in AD. Nrf2-HO-1 enhances the expression of antioxidant genes, inhibits microglia-mediated inflammation, and boosts mitochondrial function, suggesting that modulators of this protein may be useful to manage AD. This review focuses on the role of Nrf2 in AD, with a particular emphasis on the various pathways involved in the positive and negative modulation of Nrf2, namely Phosphoinositide 3-kinase (PI3K), Glycogen synthase kinase-3 (GSK-3), Nuclear factor kappa-B (NF-κB), and p38Mitogen-activated protein kinases (p38MAPK). Also, we have discussed the progress and challenges regarding the Nrf2 activators for AD treatment.

Glabridin mitigates TiO2NP induced cognitive deficit in adult zebrafish.

Glabridin is extracted from the roots of Glycyrrhiza glabra, which has anti-oxidative and anti-inflammatory properties. We investigated the neuroprotective potential of Glabridin against the learning and memory deficit by triggering NRF2/HO-1 signaling in Titanium dioxide nanoparticles (TiO2NP) treated zebrafish. Our study suggests that Glabridin at doses of 12.5, 25, and 50 mg/kg/day for 7 days improved memory and lowered anxiety in the novel object recognition test, T-maze, and novel diving tank respectively. Biochemical analysis showed that Glabridin treatment in TiO2NP-exposed zebrafish enhanced GSH, CAT, SOD, and GPx activity and reduced MDA levels; inhibited proinflammatory mediators, namely, TNF-α, IL-1ß, and IL-6. In histopathological evaluation, Glabridin significantly reduced pycnotic neurons in TiO2NP-treated zebrafish brains. Furthermore, Glabridin upregulated NRF2 and HO-1 levels, which leads to a decline in oxidative stress and neuroinflammation and were reversed by ML385 treatment. ML385 as a probe molecule that specifically inhibit NRF2 and prevents its downstream gene expression. Thus, these considerable outcomes provide new insights into the neuroprotective effect of glabridin.

Syringic acid alleviates valproic acid induced autism via activation of p38 mitogen-activated protein kinase: Possible molecular approach.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder characterized by restrictive and repetitive behavior followed by impairment in social, verbal, and non-verbal interaction and communication. Valproic acid (VPA) is a well-known anti-epileptic drug, but its prenatal exposure to animals causes social impairment, neurotransmitters imbalance, and neuroinflammation with ASD-like phenotypes. Syringic acid (SA) is a polyphenolic compound with anti-inflammatory, anti-apoptotic, antioxidant, and neuromodulator activity. The purpose of study was to investigate the protective effect of Syringic acid (SA) in prenatal VPA-treated rats through behavioral, neuroinflammation, oxidative stress, neurotransmitters, neuronal integrity, and apoptotic marker. Single dose of VPA was administered 600 mg/kg, i.p. on a gestational day (GD) 12th and SA was administrated from PnD 26th to 54th at the dose of 25, 50, and 100 mg/kg, p.o. On PnD 56th behavioral parameters (Pain sensitivity, open field test, narrow beam walks test and social impairment test) were performed and all animals were sacrificed, and brain tissue was isolated for oxidative stress (GSH, CAT, and LPO), neuroinflammation (TNF-α and IL-6) and neurotransmitters (GABA and Glutamate), histopathology (H&E, Nissl), immunohistochemistry (p38 MAPK) analysis. Rat treated with SA dose-dependently prevented behavioral alteration, restored antioxidant enzymes, neurotransmitters level, decreased neuroinflammatory markers, and improved neuronal integrity. Furthermore, immunohistochemistry confirmed the reduced p38 MAPK marker expression by SA in VPA induced autistic behavior.

Neuromodulation in Parkinson's disease targeting opioid and cannabinoid receptors, understanding the role of NLRP3 pathway: a novel therapeutic approach.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in motor and non-motor symptoms. Although levodopa is the primary medication for PD, its long-term use is associated with complications such as dyskinesia and drug resistance, necessitating novel therapeutic approaches. Recent research has highlighted the potential of targeting opioid and cannabinoid receptors as innovative strategies for PD treatment. Modulating opioid transmission, particularly through activating µ (MOR) and δ (DOR) receptors while inhibiting κ (KOR) receptors, shows promise in preventing motor complications and reducing L-DOPA-induced dyskinesia. Opioids also possess neuroprotective properties and play a role in neuroprotection and seizure control. Similar to this, endocannabinoid signalling via CB1 and CB2 receptors influences the basal ganglia and may contribute to PD pathophysiology, making it a potential therapeutic target. In addition to opioid and cannabinoid receptor targeting, the NLRP3 pathway, implicated in neuroinflammation and neurodegeneration, emerges as another potential therapeutic avenue for PD. Recent studies suggest that targeting this pathway holds promise as a therapeutic strategy for PD management. This comprehensive review focuses on neuromodulation and novel therapeutic approaches for PD, specifically highlighting the targeting of opioid and cannabinoid receptors and the NLRP3 pathway. A better understanding of these mechanisms has the potential to enhance the quality of life for PD patients.