Physical activity is known to ameliorate neuropathic pain (NP); however, the underlying mechanisms, particularly those involving long non-coding RNAs (lncRNAs) in the hippocampus, remain poorly understood. In this study, we assessed the impact of swimming training on NP in a mouse model of sciatic nerve injury (SNI), with a focus on the lncRNA H19 and its associated signaling pathway. A male C57BL/6 mouse model of SNI was established and randomly divided into five groups: naïve, sham, sham + swim, SNI, and SNI + swim. The swimming groups underwent a 6-week training regimen. Pain thresholds were assessed at multiple time points post-modeling, and hippocampal tissues were collected on day 43 for analysis. Six weeks of swimming training significantly attenuated mechanical hypersensitivity in SNI mice. Compared with the SNI group, swimming training was associated with reduced hippocampal expression of H19, Wnt3a, and β-catenin. Histological analyses using HE and Nissl staining demonstrated improved neuronal morphology and preservation of neuronal structure in the hippocampus following swimming training. In addition, swimming training modulated hippocampal neuroinflammation, as evidenced by decreased levels of IL-6 and TNF-α and increased expression of the IL-10. These findings indicate that swimming training effectively alleviates NP and hippocampal neuroinflammation in SNI mice and is accompanied by coordinated changes in hippocampal H19, miR-22, and Wnt/β-catenin signaling. These associations suggest a potential involvement of H19-related molecular responses in exercise-mediated neuroprotection; however, further mechanistic studies are required to establish causal relationships.
Hexanucleotide GGGGCC repeat expansions in C9orf72 produce arginine-rich dipeptide repeat proteins, including poly-GR and poly-PR, that contribute to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Although poly-GR has been linked to oxidative stress and mitochondrial dysfunction, the mechanisms that determine whether antioxidant defenses are preserved or suppressed in poly-GR-expressing motor neurons remain incompletely understood. Here, we investigated whether Sigma-1 receptor (Sigma-1R) modulates poly-GR-associated redox dysregulation in cellular and mouse models. In NSC34 cells, both EGFP-PR42 and EGFP-GR50 expression reduced NRF2 protein levels. EGFP-GR50 expression was also associated with reduced NRF1 and HO1 levels and increased reactive oxygen species (ROS) accumulation. Sigma-1R overexpression or pharmacological activation with fluvoxamine or PRE084 restored NRF2 and HO1 expression and attenuated both cellular and mitochondrial oxidative stress in EGFP-GR50-expressing cells. Co-treatment with the Sigma-1R antagonist NE100 attenuated the agonist-induced restoration of NRF2 and HO1. Furthermore, the NRF2 inhibitor ML385 attenuated agonist-mediated HO1 restoration, supporting the involvement of NRF2 activity in this downstream response. In an AAV-mediated EGFP-GR50 mouse model, Sigma-1R deficiency was associated with shortened survival, reduced NeuN-positive neuronal counts, and decreased NRF2 immunoreactivity in the brain. Together, these findings identify Sigma-1R as a modulator of poly-GR-associated redox dysregulation and neuronal vulnerability and support further investigation of Sigma-1R modulation as a potential therapeutic strategy for C9orf72-associated ALS.
Parkinson's disease (PD), the second most common neurodegenerative condition, develops because of abnormal protein misfolding and aggregation of α-synuclein with its subsequent intercellular spread. Such pathological changes lead to disruption of neuronal homeostasis and contribute to neuronal degeneration. During normal conditions, α-synuclein clearance is controlled by different types of lysosomal degradation, namely, macro autophagy, chaperone-mediated autophagy (CMA), micro autophagy, and the ubiquitin-proteasome system. Malfunction of these systems results in increased α-synuclein secretion due to exosome-dependent, direct, and damage-induced mechanisms, which, in turn, promotes enhanced intercellular propagation, inflammation, mitochondrial dysfunction, blood-brain barrier leakage, and neuronal cell death. Although several approaches targeting α-synuclein clearance have shown biological activity in preclinical or early clinical studies, consistent disease-modifying efficacy has not yet been established, owing to challenges including target specificity, blood brain barrier penetration, biological heterogeneity, and the limited sensitivity of clinical endpoints. Recent research indicates that successful treatment is more related to restoring the balance of these two processes than to manipulating one of them.In this review, it is proposed that a systems-level approach can be taken where PD is understood as a disease characterized by the imbalance in proteostasis. Potential treatment modalities include small molecules targeting lysosome function (ambroxol, rapamycin, TFEB activators), CMA enhancers, gene therapy, and antibodies against extracellular α-synuclein. Furthermore, new modalities like molecular glue degraders, allostery-based stabilization of α-synuclein tetramers, engineered decoy particles, and bispecific antibodies represent some other possible routes towards multimodal disease modification.
Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder with progressive cognitive decline and neuronal loss. This study investigated the neuroprotective effects of AMBMP Hydrochloride, a Wnt/β-catenin agonist, in a streptozotocin (STZ)-induced mice model of AD, elucidating the interplay between dysregulated Wnt/β-catenin signaling and Toll-Like Receptor 4 (TLR4)-mediated inflammation, with Palmitic acid used as a TLR4 pathway modulator. Mice received bilateral intracerebroventricular (i.c.v.) injections of STZ (3 mg/kg) on Day 1 and Day 3, followed by administration of Donepezil (3 mg/kg)/ AMBMP Hydrochloride (5 mg/kg and 10 mg/kg)/Palmitic acid (TLR4 agonist, 20 mg/kg) via the intraperitoneal (i.p.) route from Day 4 to Day 22. STZ-treated mice exhibited significant cognitive dysfunction, characterized by impaired performance in the Morris Water Maze (MWM) task along with increase in acetylcholinesterase (AChE) activity, oxidative stress (thiobarbituric acid reactive substances; TBARS), neuroinflammation [tumor necrosis factor alpha (TNF-α)/Interleukin-6 (IL-6)/Interleukin-1 beta (IL-1β) and nuclear factor kappa B (NF-κB)] and decreased reduced glutathione (GSH) levels. However, AMBMP Hydrochloride significantly improved behavioral and biochemical alterations possibly through modulation of Wnt/β-catenin signaling and attenuation of TLR4-mediated inflammation. Interestingly, Palmitic acid co-treatment was found to counteract these protective effects, further pointing to a role of TLR4 in the pharmacological effect of AMBMP Hydrochloride. In summary, we confirmed that AMBMP Hydrochloride exhibits potent neuroprotective effects associated with modulating Wnt/β-catenin/TLR4 signaling, offering a promising therapeutic approach against Alzheimer-Type Dementia. Future studies should delve deeper into the molecular mechanisms and translational promise of AMBMP hydrochloride, paving the way for its development as a potential candidate for AD management.
Perioperative neurocognitive disorder (PND) manifests as neurocognitive alterations induced by anesthesia and surgical stress. High-risk factors, including advanced age, obesity, diabetes, and preoperative neurological dysfunction, accelerate PND progression, with neuroinflammation serving as a core pathological mechanism throughout PND pathogenesis. Semaglutide regulates neuroinflammation in patients with diabetes and stroke, yet its role in PND remains undefined.A lipopolysaccharide (LPS)-induced inflammatory neurocognitive impairment mouse model was established via intracerebroventricular injection. Mice were treated with semaglutide alone or combined with the O-GlcNAc transferase inhibitor OSMI-1 and AKT-silencing adeno-associated viruses. Behavioral, biochemical and immunofluorescence assays were performed to evaluate cognitive function and molecular changes. Semaglutide significantly rescued LPS-induced cognitive deficits and restored hippocampal O-GlcNAcylation. Mechanistically, LPS inhibited AKT O-GlcNAc modification and AKT-mTOR pathway activity, facilitated mTOR-gephyrin binding, disrupted GABAAR distribution, aggravated neuronal apoptosis, and impaired synaptic plasticity. Semaglutide reversed these abnormalities by elevating AKT O-GlcNAcylation to activate the AKT-mTOR pathway, which triggered mTOR-gephyrin dissociation, restored synaptic GABAAR localization, attenuated neuronal damage, and rescued synaptic plasticity.Semaglutide ameliorates PND via AKT O-GlcNAcylation-mediated AKT-mTOR activation and subsequent neuroprotective effects.
