Neurotherapeutics最新文献

Alzheimer's disease (AD), closely associated with mitochondrial dysfunction, currently lacks convenient and non-invasive biomarkers for mitochondrial assessment. In this study, we developed an artificial intelligence framework leveraging live urine-derived stem cell (USC) mitochondrial fluorescence imaging to investigate differences between cognitively impaired individuals (AD and mild cognitive impairment (MCI)) and cognitively normal (CN) subjects. Mitochondrial fluorescence images from living HeLa cells were first segmented, and two binary classification models based on the ResNet-18 convolutional neural network were trained to identify mitochondrial hyperfission and hyperfusion relative to normal morphology. The models demonstrated robust performance in detecting intermediate mitochondrial states during validation. When applied to USCs, the system effectively distinguished mitochondrial patterns associated with cognitive impairment, highlighting its potential for the early detection of Alzheimer's disease and merits further validation in larger, independent cohorts.

More than half of subarachnoid hemorrhage (SAH) survivors develop delayed cognitive dysfunction, but the underlying mechanisms remain elusive. This study investigated the role of meningeal lymphatic vessels (mLVs) in this complication by examining their structural integrity, drainage capacity, and association with cognitive deficits post-SAH. In adult male C57BL/6J mice in which SAH was induced by intracisternal injection of autologous blood, spatial learning and memory, and hippocampal CA1 neuronal activity were impaired as early as 1 month post-surgery, with a marked exacerbation of these deficits at 2 months. SAH induced mLV fragmentation and atrophy, subsequent cerebrospinal and interstitial fluid drainage impairment, metabolite accumulation, and ultimately delayed cognitive dysfunction. Notably, lymphatic vessel ablation exacerbated these pathologies. In vitro experiments confirmed that vascular endothelial growth factor C (VEGF-C) reduced oxyhemoglobin-induced lymphatic endothelial cell apoptosis. Furthermore, in vivo studies demonstrated that VEGF-C therapy inhibited amyloid-β (Aβ) deposition in the hippocampal CA1 region and ameliorated cognitive dysfunction. Additional studies revealed that VEGF-C's protective effect on mLVs may be mediated via PI3K-AKT pathway activation. Collectively, these findings indicate that disrupted mLV integrity and drainage contribute to post-SAH cognitive impairment. Activation of VEGF-C-mediated PI3K-AKT signaling may preserve mLV function and represent a potential therapeutic strategy for preventing delayed cognitive impairment after SAH.

Several studies show that neurosteroids currently play a significant role in autism spectrum disorders (ASD). However, the pathway of neurosteroid synthesis involved in ASD remains unclear. This study aimed to investigate the crosstalk between autism and neurosteroids, focusing on the mechanism of allopregnanolone production. We used the BTBR T+ tf/J (BTBR) mouse, a well-established animal model of ASD that exhibits typical autism-like behaviors along with neuroinflammation. In the hippocampus of BTBR mice, we observed a marked overexpression of pregnenolone and a related reduction in allopregnanolone levels. This neurosteroid imbalance also appears to be associated with an inflammatory pattern and the manifestation of repetitive and asocial behaviors. The combination of low doses of ultramicronized palmitoylethanolamide (PEA-um) and docosahexaenoic acid (DHA) restores allopregnanolone production modulating neurosteroidogenesis. In association with neurosteroid modulation, this restoration reduces repetitive behaviors and improves social interactions in BTBR mice, also modulating the inflammatory profile with a significant reduction in proinflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels in the hippocampus. These effects demonstrate an important role of the peroxisome proliferator-activated receptor alpha (PPAR-α), whose expression is particularly reduced in BTBR mice. In addition, the pivotal involvement of PPAR-α was further supported by administering a specific antagonist that abolished the advantageous effects of PEA-um ​+ ​DHA. Overall, our findings demonstrate the potential synergistic effect of the low-dose combination of PEA-um and DHA, confirming their therapeutic effect in ASD and the involvement of neurosteroids in their mechanism of action.

Primary adult-onset neurodegenerative cerebellar ataxias (PANCA) are a clinically and genetically diverse group of disorders for which disease-modifying therapies remain limited. In this review, we provide a comprehensive analysis of therapeutic strategies for PANCA, with a primary focus on clinical trials-randomized controlled and open-label-that have evaluated pharmacological agents, rehabilitation programs, and neuromodulatory interventions. Where clinical trial data are lacking, we incorporate relevant observational studies, expert consensus, and mechanistic rationale to contextualize current practices. Rehabilitation and multidisciplinary care remain foundational across all subtypes and are supported by growing clinical trial evidence. Pharmacological approaches, including omaveloxolone for Friedreich's ataxia and off-label agents such as riluzole, 4-aminopyridine, and varenicline, demonstrate subtype-specific benefits. Neuromodulation techniques, such as transcranial direct current stimulation and repetitive transcranial magnetic stimulation, have shown early promise in improving motor outcomes. In parallel, molecular and gene-based therapies-including antisense oligonucleotides, viral vector delivery systems, and CRISPR-based strategies-are advancing into preclinical and early-phase clinical studies. This evolving therapeutic landscape underscores a shift toward personalized, multimodal care for cerebellar ataxias and highlights the need for continued translational efforts to bridge mechanistic insights with clinical impact.

Intracerebral hemorrhage (ICH) is a highly fatal stroke subtype with limited treatment options, where pathological activation of peri-hematomal microglia drives acute secondary injury. Colony-stimulating factor 1 receptor (CSF-1R), highly expressed in microglia, is a potential therapeutic target. This study evaluated the effects of short-term administration of sunitinib, a clinically used CSF-1R inhibitor, in a collagenase-induced mouse ICH model and an in vitro hemoglobin (Hb)-treated BV2 microglial model. Sunitinib significantly improved motor functions, reduced myelin damage, and attenuated microglial activation and neuroinflammation in peri-hematomal tissue. RNA sequencing revealed that sunitinib might modulate lipid metabolism, phagocytosis, and immune response. In BV2 cells, sunitinib inhibited Hb-induced lipid droplet accumulation, phagocytic reduction, and pro-inflammatory cytokine production, effects mirrored by CSF-1R knockdown. These findings suggest that sunitinib alleviates acute ICH injury by modulating microglial functions, likely through inhibition of the CSF-1R axis, supporting its potential repurposing for central nervous system disorders like ICH.

Substance use disorder (SUD) remains a critical public health issue characterized by high rates of relapse and limited effective pharmacotherapies, particularly for non-opioid substances. A key challenge in addressing SUD lies in the persistent neuroadaptations within the brain's reward circuitry. The endocannabinoid (eCB) system plays a crucial role in modulating reward and reinforcement processes and is disrupted by chronic drug exposure. Recent work highlights the therapeutic potential of indirectly modulating cannabinoid 1 (CB1) receptor signaling by targeting eCB-metabolizing enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), to restore homeostatic eCB tone. We review and synthesize findings from both genetic and pharmacological studies, highlighting the contributions of FAAH and MAGL across major classes of abused substances and considering their potential as therapeutic targets for SUD treatment.

Anti-CD20 antibodies and cladribine are established therapies for active relapsing multiple sclerosis (RMS). Increasing evidence suggests that switching between these therapies may be beneficial in patients with ongoing disease activity under current treatment. In this multicenter retrospective study across six German MS centres, a total of 90 patients with active RMS were considered for inclusion, of whom 71 patients were switched either from anti-CD20 antibodies to cladribine (n ​= ​31) or from cladribine to anti-CD20 antibodies (n ​= ​40), with a minimum follow-up of 12 months. At treatment initiation, patients switching from anti-CD20 antibodies were older, had a longer disease duration, and a higher disability score compared to those switching from cladribine (p ​= ​0.0040, p ​= ​0.0447, p ​= ​0.0028, respectively). The primary reason for switching was disease activity. Following the switch, the proportion of patients with relapsing disease activity was markedly reduced (from 55 ​% to 16 ​% for anti-CD20 to cladribine, and from 83 ​% to 25 ​% for cladribine to anti-CD20). Clinical outcomes improved, while serum biomarkers such as neurofilament light chain and glial fibrillary acidic protein remained stable over six months. Notably, the prevalence of hypogammaglobulinemia decreased after switching from anti-CD20 therapies to cladribine. These results indicate that patients with active RMS can achieve clinical stabilization after switching therapies in either direction, underscoring the complementary mechanisms of action and the safety of such an approach in real-world practice.

Lafora disease (LD) is a fatal progressive myoclonus epilepsy that affects previously healthy adolescents and lacks effective treatments. It is caused by pathogenic variants in EPM2A or NHLRC1, leading to the accumulation of polyglucosan in the brain and other tissues. This study is the first to evaluate the administration of a potentially disease-modifying drug - VAL-1221, a glycogen-degrading antibody-enzyme fusion - in LD patients through a 12-month compassionate use program. Five patients (aged 17-24 years; three females) with intermediate to advanced LD received VAL-1221 intravenous infusions (20 ​mg/kg every other week). Safety was monitored through treatment-emergent adverse events (TEAEs), whereas efficacy was assessed using clinical scales, EEG and neuroimaging. Drug concentration profile was studied via liquid chromatography-high resolution mass spectrometry (LC-HRMS) of plasma and cerebrospinal fluid (CSF), and metabolomics via gas chromatography-MS of CSF. Four patients completed the full treatment course: one discontinued after eight months following status epilepticus. VAL-1221 was well tolerated, with five mild infusion-related TEAEs (skin rash in one, hypotension in four). Efficacy measures showed continued disease progression across patients. LC-HRMS analysis revealed no detectable levels of VAL-1221 in CSF. CSF metabolic profiling revealed no difference between untreated and VAL-1221-treated samples. These findings demonstrate that intravenous VAL-1221 is safe but ineffective, providing an important negative result that prevents further patient exposure to this approach and redirects efforts toward direct central nervous system delivery methods. The study also demonstrates the feasibility of assessing disease progression using clinical and neuroimaging measures, providing a valuable framework for clinical trials in LD.