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[Display omitted] Traumatic brain injury (TBI) triggers a bevy of changes including mitochondrial dysfunction, apoptosis, oxidative stress, neurobehavioural impairment, and neuroinflammation, among others. Dantrolene (DNT), a muscle relaxant which inhibits intracellular Ca2+ signaling from the ER, has been repurposed as a potential neuroprotective agent in various neurological diseases. However, there have been limited studies on whether it can mitigate TBI-induced deficits and restore impaired mitochondrial dynamics. This study sought to evaluate whether Dantrolene can potentially provide neuroprotection in an in vivo model of TBI. Male wistar rats subjected to TBI were treated with DNT (10 mg/kg) 1 h and 12 h post surgery. Animals were assessed 24 h post-TBI to evaluate neurobehavioural deficits and cerebral edema. We evaluated the protein expressions of apoptotic, autophagic, and neuroinflammatory markers by immunoblotting, as well as Mitochondrial Membrane Potential (MMP) and Reactive Oxygen Species (ROS) via Flow Cytometry to ascertain the effects of DNT on TBI. We further analysed immunofluorescence staining with Glial Fibrillary Acidic Protein (GFAP) and immunohistochemistry with NF-κβ to investigate neuroinflammation. H&E staining was also performed post-TBI. Our findings revealed DNT administration inhibits mitochondria-mediated apoptotis and reduces heightened oxidative stress. DNT treatment was also found to reverse neurobehavioural impairments and offer neuroprotection by preserving neuronal architechture. We also demonstrated that DNT inhibits neuronal autophagy and alleviates neuroinflammation following TBI by modulating the NF-κβ/Akt signaling pathway. Thus, our results suggest a novel application of DNT in ameliorating the multitude of deficits induced by TBI, thereby conferring neuroprotection. [ABSTRACT FROM AUTHOR]

Ropinirole (ROP) is a dopamine agonist that can cross the blood-brain barrier (BBB), which is crucial for drugs targeting neurological conditions like Alzheimer's disease (AD). The rationale for the current research is to investigate the potential of ROP as an inhibitor of Microtubule affinity regulating kinase 4 (MARK4)-NFκβ in neurodegenerative diseases, specifically AD. The interaction between ROP and MARK4-NFκβ holds significant promise in the realm of drug discovery and therapeutic interventions for diseases like AD. Molecular docking and biophysical characterization demonstrate how ROP effectively hinders MARK4 activity, offering detailed insights into their molecular interactions. The present research also investigates the biological aspect of MARK4 shows promise in treating AD, with neuroinflammation playing a crucial role in the disease's progression. Aβ 42 and ROP were co-administered directly into the cells for the establishment of the AD model. We confirmed that ROP can inhibit the path of MARK4 activity, as evidenced by biophysical characterization, and can enhance the cell viability, lowers the expression of MARK4, decrease the rate of oxidative stress, and attenuate the expression of NFκβ, leading to reduced neuronal apoptosis in an in vitro -induced Aβ model. Overall, this research provides valuable mechanistic insights into the neuroprotective potential of ROP and its ability to target the MARK4-NFκβ pathway. The amyloid hypothesis (AH) suggests that Alzheimer's disease (AD) begins with the breakdown of amyloid precursor protein (APP) by β-secretase (BACE1), forming APP carboxyl-terminal fragments (CTFs). Subsequent processing by γ-secretase produces Aβ, leading to the formation of senile plaques in the extracellular space involving proteoglycans and apolipoproteins. Extracellular Aβ oligomers can trigger caspases via cell surface receptors, while intracellularly, Aβ may activate caspases through endoplasmic reticulum or mitochondrial stress. Immune response dysregulation can harm cells at a molecular level, releasing inflammatory markers and reactive oxygen species, culminating in cell death and plaque development in AD. The NFκβ and MARK4 pathway is highlighted as a key contributor to AD pathogenesis. [Display omitted] • Biophysical/kinetic confirming that ROP has inhibitory potential in the path of MARK4 activity. • The neuroprotective efficacy of ROP against the Aβ 42 model by enhancing cell viability • Lowering the expression of MARK4 can reduce oxidative stress and neuronal apoptosis by attenuating the NF-κB pathway. • The findings suggest that MARK4 inhibition can be a potential therapeutic approach for managing MARK4-associated diseases [ABSTRACT FROM AUTHOR]