ハンチントン病

Morin (3,5,7,2',4'-pentahydroxyflavone) is a dietary flavonol with broad neuroprotective, anti-inflammatory, and antioxidant actions across central and peripheral nervous system models. This synthesis consolidates evidence from in vitro and rodent studies-covering neurodegenerative proteinopathies (Alzheimer's, Parkinson's, and Huntington's), neuropathic pain, epilepsy, stress- and schizophrenia-like phenotypes, and chemo-/toxicant-induced neurotoxicity-to evaluate morin's consistent benefits on survival, motor/cognitive performance, and biochemical normalization. Morin mitigated neurotoxicity induced by doxorubicin, ifosfamide, vincristine, acrylamide, heavy metals, and endocrine disruptors. Context-specific effects included modulation of disease-defining pathways (GSK3β/CDK5, mTORC1, PARP, and AMPK-ULK1-TFEB), microglial polarization, and normalization of neurotransmission (dopamine, GABA, 5-HT, and reduced AChE). Core mechanisms included the following: restoration of redox and mitochondrial homeostasis via Nrf2/HO-1 activation; replenishment of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH); decreased reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO); and preserved mitochondrial potential/fusion; suppression of innate immune and inflammasome signaling through downregulation of TLR4/NF-κB and ERK-p65, reduced TNF-α, IL-1β/IL-6, iNOS/COX-2; inhibition of NLRP3/caspase-1; and rebalancing of cell-death programs (↓Bax/caspase-3, ↑Bcl-2; attenuation of RIPK1/RIPK3/MLKL-mediated necroptosis). Formulation strategies (intranasal microemulsions, pluronic micelles, and more soluble derivatives) have enhanced brain exposure and efficacy, but translation now warrants optimized delivery, pharmacokinetic-pharmacodynamic mapping, target engagement biomarkers, and rigorously controlled trials to define dose, route, and indications as adjunctive to standard care in neurodegeneration, neuropathic pain, and toxicant-related brain injury. Collectively, morin emerges as a multitarget neuroprotective scaffold with reproducible functional and mechanistic benefits.

Drug repurposing refers to the process of using an existing drug or drug candidate for a new treatment or medical condition for which it was not indicated before. The process of "drug repurposing" usually involves an FDA-approved entity which has undergone clinical development and have a with well-established safety and toxicity profile in patients. Several convergent studies show that repurposed drugs may present a promising strategy for the management and therapy of several human cancers. Memantine is used to combat dementia in moderate-to-severe Alzheimer's disease (AD) patients. Several convergent studies show that memantine (and its analogs) may have applications in multiple disease conditions associated with human cancers. Memantine and its related compounds have shown promise as neuroprotective agents, anti-fatigue agents and pain-relieving agents to alleviate the toxic side effects of radiation therapy and chemotherapy. Recent publications have revealed that memantine displays anti-cancer activity by exerting direct growth-suppressive activity on the primary tumor as modulating the genomic/cellular landscape of the tumor microenvironment. Currently, clinical trials are in progress, which aim to evaluate the potential applications of memantine in cancer treatment. The adamantane scaffold in memantine has proved to be a versatile tool for the discovery of synthetic memantine analogs with robust anti-cancer activity. The discovery of second-generation memantine analogs may have wider applications in combating cancer recurrence and addressing clinical challenges in the treatment of drug-resistant and metastatic cancers.

BACKGROUND: Neurodegenerative diseases may continue to progress even when a pathogenic protein aggregate is reduced, suggesting that downstream inflammatory and genotoxic circuits can become partly autonomous. This narrative review examines cGAS-STING as a context-dependent regulator of DNA-stress responses in the ageing and proteinopathic brain. METHODS: PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar were searched for mechanistic, translational, and human-tissue studies of cGAS-STING, DNA damage, mitochondrial quality control, neuroinflammation, and major neurodegenerative diseases. Evidence was separated into biochemical or cellular, animal, and human observations, and contradictory findings were retained. RESULTS: Mitochondrial DNA leakage is a recurrent candidate trigger, while activity-induced nuclear DNA breaks, defective repair, retrotransposon-derived cDNA, and micronuclear rupture provide conditional inputs. Microglial evidence is currently more extensive and causally developed than neuron-specific evidence; neuronal STING is most firmly supported in selected contexts such as excitotoxic or ischemic stress. Across Alzheimer disease, Parkinson disease, ALS/FTD, multiple sclerosis, and Huntington disease, cGAS-STING-associated inflammation is plausible but not uniform, and human validation remains limited. Therapeutic strategies therefore require cell-, source-, and stage-aware modulation rather than indiscriminate pathway ablation. CONCLUSION: cGAS-STING is best regarded as a testable kinetic-bottleneck model, not a universal driver of neurodegeneration. Longitudinal human studies and cell-resolved biomarkers are needed to determine when recalibration can suppress pathological inflammation while preserving antiviral and homeostatic functions.

Dopamine neuromodulation is a critical process that facilitates learning, motivation, and motor control. Disruption of these processes has been implicated in several neurodegenerative disorders including Huntington's Disease (HD). While dopaminergic signaling is a therapeutic target for treating physical and psychiatric HD symptoms, the mechanism by which dopaminergic dysfunction occurs during HD is unknown. New tools for the visualization of dopamine dynamics at the spatiotemporal resolution of neuromodulator release (ms) and dopaminergic boutons (µm) provide a richer understanding of how dopamine signaling is disrupted in HD. Here we employ near-infrared fluorescent catecholamine nanosensors (nIRCats) to image dopamine release within the striatum of R6/2 Huntington's Disease model mice of either sex. We find that dorsal striatal dopamine release decreases with progressive degeneration and that these deficits are primarily driven by a decrease in the number of nIRCat imaged dopamine release sites, termed dopamine hotspots, combined with decreased release fidelity. Using nIRCat's high spatial resolution, we track individual dopamine hotspots over repeated stimulations and pharmacological applications to measure dopamine release fidelity from individual sites. Compellingly, we found that D2-receptor (D2R) antagonist sulpiride drives increased fidelity of dopamine hotspot activity in wild type striatum but not in late-disease HD striatum, suggesting that D2R regulation of dopamine release is compromised in late HD. These findings, enabled by nIRCats, provide more detailed insights into how dopamine release is disrupted and dysregulated during Huntington's Disease.Significance statement Huntington's Disease (HD) is a neurodegenerative disorder with no cure. Dopamine signaling is known to deteriorate in HD but has not been studied at the level of individual release sites. Here, we image dopamine release from individual dopamine release sites in R6/2 HD mouse brain slices containing the striatum with novel dopamine nanosensors. We find that dopamine release site number and release fidelity are decreased in late HD. Furthermore, we demonstrate that D2-receptor signaling may be altered in late disease R6/2 HD mice, and that these disruptions are likely to drive decreased dopamine release fidelity over multiple stimulations. These findings suggest dopaminergic neurons projecting to the striatum as a potential therapeutic target for HD treatment to complement more commonly targeted medium spiny neurons.

We are in an era in which increasing numbers of potentially disease-modifying treatments for Parkinson's disease are being tested in clinical development. Current definitions of disease modification have inherent limitations; hence there is a need to establish a clear, unified definition. This unified definition of disease modification should be applicable to both idiopathic and genetic forms of Parkinson's disease. In addition to motor function, it must address important milestones (e.g., cognition, autonomic dysfunction) across all disease stages. This review examines existing definitions and highlights the need for a more holistic approach that integrates the perspectives of patients, healthcare professionals, and researchers.