Neurotherapeutics最新文献

Dysregulation of cholesterol metabolism and neuroinflammation are critical drivers of Amyotrophic Lateral Sclerosis (ALS) pathology. Liver X receptors (LXRs) are master regulators of cholesterol homeostasis and immune responses. Here, we evaluated the therapeutic potential of chronic pharmacological modulation using the potent synthetic agonist T0901317 (T0) in the hSOD1^G93A mouse model. To assess both long-term functional outcomes and the underlying molecular mechanisms, T0 was administered via two distinct experimental designs. In a longitudinal cohort treated from postnatal day 60 (P60) until the humane endpoint, T0-treated SOD1G93A mice exhibited delayed body weight loss and sustained improvements in neuromuscular strength and motor coordination. Critically, this continuous treatment preserved functional motor unit connectivity, delayed overall clinical progression, and significantly extended median lifespan. While protective in both sexes, the survival benefit was slightly more pronounced in females. Molecular characterization revealed that the early systemic T0 administration successfully engaged canonical LXR targets in the spinal cord, driving a significant transcriptional upregulation of cholesterol efflux pathways and suppressing pro-inflammatory signaling cascades. This response induced a lipid partitioning, evidenced by a significant accumulation of cholesterol esters within the central nervous system, potentially mitigating lipotoxicity. Taken together, these findings demonstrate that T0901317 treatment exerts a significant beneficial effect, highlighting the pharmacological modulation of these lipid and inflammatory networks as a promising therapeutic strategy for ALS.

Brain metastases (BM) are a common and clinically significant manifestation of advanced cancer that increasingly influences treatment decisions across solid tumors. Management requires a tailored approach because intracranial disease may behave differently from extracranial disease, reflecting differences in drug penetration, blood-brain barrier biology, and the local immune milieu. This review summarizes the current biologic and clinical framework of BM, including molecular divergence from the primary tumor, the evolution of prognostic models, and the growing role of brain-specific risk stratification in treatment planning. It also reviews contemporary evidence for systemic therapies with intracranial activity across major tumor types, with particularly important advances in oncogene-driven non-small cell lung cancer, human epidermal growth factor receptor 2-positive breast cancer, melanoma, and renal cell carcinoma. In addition, the review examines the integration of systemic therapy with local approaches such as stereotactic radiosurgery, where safety appears to be more agent-specific than timing-specific. Emerging strategies, including focused ultrasound-mediated blood-brain barrier opening and tumor treating fields, may further broaden therapeutic possibilities. The management of BM increasingly depends on a multidisciplinary, biologically informed approach supported by more consistent intracranial endpoints and dedicated central nervous system-focused research.

Subthalamic stimulation in Parkinson's disease may operate by suppressing high-beta connectivity along the hyperdirect pathway and by promoting gamma motor cortical processing. We examined how the phase of beta activity shapes the amplitude of the gamma rhythm along hyperdirect connections and how stimulation influences this coupling. Thirty-eight patients with akinetic-rigid Parkinson's disease treated with bilateral subthalamic stimulation were recruited. A high-density electroencephalogram was recorded at rest and while patients drew self-paced and traced spirals on a digital tablet at four stimulation levels. We analyzed time-resolved phase-amplitude coupling between low (13-20 Hz) and high beta (21-30 Hz) and low (31-60 Hz) and high gamma (61-100 Hz) frequency band pairs between the subthalamic nucleus and motor cortical areas. The stimulation-induced decreases in phase-amplitude coupling were correlated with real-time improvement in bradykinesia and predicted by clinical factors. Among the subthalamic beta-cortical gamma bands, the high beta-high gamma phase-amplitude coupling was the largest (p < 0.001), and decreased the most at the highest stimulation level (p < 0.001), in correlation with the improvement in bradykinesia. Its stimulation-induced decrease could be predicted in task-specific pathways consisting of the primary motor cortex and the dorsal premotor cortex; the rate of improvement in drawing speed and the active contact locations were the key predictors. Phase-amplitude coupling of the cortical beta-subthalamic gamma band pairs did not respond to stimulation. Subthalamic stimulation selectively interferes with the subthalamic high beta-driven cortical gamma block in task-specific pathways in Parkinson's disease, tracking the improvements in bradykinesia.