Neurotherapeutics最新文献

Synaptic loss is strongly associated with cognitive decline in Alzheimer's disease (AD). Endosomal trafficking dysfunction, observed in AD brains, impairs neurite growth. Because endosomal trafficking is essential for synaptic development, we selected LMTK1, a negative regulator of Rab11/RE pathway, for this study, given its upregulation in AD models. Clinical genomic data from the ADNI ​(Alzheimer's Disease Neuroimaging Initiative) database were analyzed to evaluate the relationship between LMTK1 and AD. Two AD mouse models, 3xTg and SAMP8, were examined for neurite outgrowth, synaptic density, LMTK1 expression, and recycling endosomes (RE) transport. LMTK1 knockdown was achieved using AAV. The Morris water maze, Golgi staining, immunofluorescence, and electrophysiology experiments were used to assess cognitive function, neurite outgrowth, synaptic density, RE transport, long-term potentiation (LTP), and synaptic transmission. The mechanism of LMTK1 in regulating RE transport was examined through co-immunoprecipitation, proteomics, and point mutation experiments. This study shows that phosphorylated LMTK1 activates TBC1D9B, which deactivates Rab11a and may suppress Rab11a⁺ endosome trafficking and neurite growth. Clinical genomics data from the ADNI database support LMTK1's involvement in cognition in AD and possibly in glucose hypometabolism related to synaptic dysfunction. Knocking down LMTK1 improves neurite atrophy and synaptic density loss, likely by enhancing Rab11⁺ endosome transport. Restoration of neurite morphology, hippocampal LTP, and cognitive function in AD mice suggest that inhibiting LMTK1 could represent a novel therapy for promoting neurite growth in AD. Hyperphosphorylation of LMTK1 may induce RE transport dysfunction, leading to neurite atrophy in AD mice. Therefore, targeting LMTK1 may offer a promising therapeutic approach for AD therapy.

Abnormal accumulation of α-synuclein in neuronal and/or glial cells occurs in a range of neurodegenerative conditions, including Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, and multiple system atrophy. Immunotherapy targeting α-synuclein is a rational treatment strategy for these α-synucleinopathies. Exidavnemab (also known as BAN0805 or ABBV-0805) is a monoclonal antibody with a high affinity and selectivity for pathological aggregated forms of α-synuclein, and a low affinity for physiological monomers. Exidavnemab is presently in clinical development as a disease-modifying treatment for patients with α-synucleinopathy. To provide information relevant to human target engagement, the present study investigated exidavnemab binding ex vivo using human post mortem brain tissues. Immunohistochemistry experiments demonstrated that exidavnemab bound to aggregated α-synuclein in tissues from individuals affected by Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, and multiple system atrophy. Immunoprecipitation using exidavnemab effectively removed α-synuclein aggregates from Triton-soluble brain tissue extracts. Data from these ex vivo studies using human tissues are consistent with clinical findings and provide further support for the continued development of exidavnemab as a potential treatment for multiple forms of α-synucleinopathy.

Chronic sleep deprivation (SD) is a prevalent and modifiable risk factor that accelerates neurodegeneration and exacerbates cognitive decline in Alzheimer's disease (AD). Here, we demonstrate that 808 ​nm transcranial near-infrared (tNIR) therapy reverses cognitive impairment in tauopathy mice subjected to chronic SD through multi-level molecular and circuit restoration. Behavioral and electrophysiological assessments revealed that tNIR reinstated hippocampal-dependent memory and long-term potentiation. Multi-omics profiling uncovered that tNIR orchestrates a coordinated remodeling of GPCR-cAMP-CREB signaling, synaptic vesicle cycling, and excitatory-inhibitory neruotransmission, encompassing glutamatergic, GABAergic, and retrograde endocannabinoid pathways. Lipidomic analyses identified selective remodeling of membrane microdomains, with phospholipids such as MGDG(16:0/20:2) and LPC(20:4) positively correlating with genes governing calcium signaling, vesicle dynamics, and synaptic plasticity. In parallel, tNIR suppressed stress-associated lipid-gene networks linked to oxidative damage and apoptosis. Proteomic data revealed upregulation of antioxidant enzymes (e.g., SOD2) and suppression of pro-apoptotic mediators, supporting mitochondrial resilience. Collectively, these multi-omics signatures converge on restored neurotransmitter turnover, stabilized excitatory-inhibitory balance, and reestablished a synaptically supportive microenvironment. This study provides the first evidence that tNIR therapy counteracts the compounded effects of chronic sleep deprivation and tau pathology on memory, thereby establishing a clinically relevant dual-burden framework for investigating sleep-neurodegeneration interactions. Our findings position tNIR as a non-invasive, systems-level neuromodulatory approach for mitigating sleep-related cognitive vulnerability in neurodegeneration.

Memory impairment is among the most disabling features of depression and schizophrenia, yet remains largely untreated by available pharmacotherapies. NMDA receptor hypofunction is strongly implicated in these deficits, while sigma-1 receptors, by stabilizing calcium signaling and supporting glutamatergic plasticity, have emerged as a promising therapeutic target. HBK-15, a methoxyphenylpiperazine derivative with a multimodal receptor profile, had previously shown preliminary anti-amnesic activity in rodents, prompting us to test its efficacy under NMDA receptor hypofunction. We therefore investigated whether HBK-15 engages sigma-1 receptors and restores memory in a mouse model of MK-801-induced impairment. HBK-15 bound sigma-1 receptors with high affinity and showed functional agonist activity in the BiP assay. Behaviorally, HBK-15 reversed MK-801-induced recognition and spatial memory deficits across acquisition and retrieval phases, similar to encoding and delayed recall in clinical settings. In contrast, vortioxetine and lurasidone showed only limited benefits, highlighting the broader effectiveness of HBK-15. Its ability to reverse memory impairment depended on sigma-1 receptor activity, emphasizing this pathway as a key therapeutic target. Mechanistically, HBK-15 increased hippocampal glutamatergic and cholinergic signaling under NMDA blockade, restored long-term potentiation, and improved disrupted theta-gamma coupling, a network correlate of hippocampal memory function. These findings offer experimental evidence that HBK-15 activates sigma-1 receptors to enhance hippocampal plasticity at both synaptic and network levels and to improve memory under NMDA hypofunction. Taken together, our results highlight sigma-1-based strategies as a tractable avenue for developing treatments targeting cognitive symptoms in depression and schizophrenia.

We conducted a randomized sham-controlled clinical trial from 2019 to 2024 to characterize the safety and efficacy of applying paired-associative stimulation (PAS), consisting of high-intensity transcranial magnetic stimulation and high-frequency peripheral nerve stimulation, at early stages after incomplete spinal cord injury (SCI) to enhance motor recovery. Patients with incomplete cervical SCI were randomized 1:1 within 1-4 months post-injury to receive 12 weeks of PAS or sham stimulation alongside conventional rehabilitation, which was not changed. Patients were followed up to 1.5 years after injury (about 1 year after end of stimulation). Seventeen patients (14 males, age 53 ​± ​16 years) participated. Manual Muscle Test revealed a significant effect of treatment in favor of active group (F (1, 470) ​= ​14.69; p ​< ​0.001) in muscles that had no antigravity activity before beginning of stimulation. Improvement from baseline was observed at the end of stimulation (active: 346 ​± ​53 ​%, sham: 215 ​± ​26 ​%), 1 year after injury (about 6 months after end of treatment; active: 389 ​± ​61 ​%, sham: 241 ​± ​39 ​%), and at 1.5 years after injury (about 12 months after end of treatment; active: 419 ​± ​73 ​%, sham: 210 ​± ​17 ​%). Greater improvement in fine motor skill tests was observed in the active group. Although the Spinal Cord Independence Measure showed no differences between groups (p ​= ​0.36-0.83), there was improvement in activity of daily living tests. The intervention was feasible and well-tolerated in both groups. PAS is a safe and feasible therapy that can be added to conventional rehabilitation even in early stages after SCI.

Eating disorders, including anorexia nervosa (AN), bulimia nervosa (BN), binge-eating disorder (BED), and avoidant/restrictive food intake disorder (ARFID), are serious psychiatric illnesses treated primarily with psychotherapy focusing on eating behaviors. Pharmacotherapy is recommended when psychotherapy is insufficient or unavailable, or when medication treatment is preferred by the patient. Differing psychotherapeutic approaches are used depending on the illness. Family-based treatment has demonstrated utility in adolescents with AN and BN. Eating disorder-focused cognitive behavioral therapy (CBT) is consistently helpful in individuals with BN and BED. Adaptations of CBT appear promising for the treatment of ARFID. Only two medications have received FDA approval for the treatment of eating disorders - fluoxetine for BN and lisdexamfetamine for BED. Existing treatments are not universally effective, and relapse rates are still elevated among those who do respond to treatment. Psychotherapies such as the habit-interrupting REACH ​+ ​for AN and biological treatments including neuromodulation techniques that target specific brain regions implicated in the development and maintenance of eating disorders warrant further study.

Accumulating evidence suggests that ferroptosis and mitochondrial dysfunction contribute significantly to brain injury following cardiac arrest (CA) and resuscitation. SS-31, a novel mitochondria-targeting peptide, has demonstrated protective effects against mitochondrial dysfunction induced by ischemia/reperfusion injury. This study aimed to investigate the neuroprotective effects of SS-31 in post-CA brain injury and clarify the underlying signaling mechanisms. An in vivo rat model of CA and resuscitation was established. Following resuscitation, animals were randomly divided into three groups: a saline-treated control group, an SS-31-treated group, and a sham-operated control group. Survival rates, neurological deficit scores, serum neuronal injury markers (NSE and S100B), and histopathological changes were evaluated for up to 72 ​h post-resuscitation. Mechanistically, ferroptosis-related signaling pathways were examined, including glutathione peroxidase 4 (GPX4) expression, iron accumulation, oxidative stress markers, and pro-inflammatory cytokine levels, utilizing microglia-specific Sesn2 knockdown via adeno-associated virus vectors. In vitro experiments were performed on BV2 cells subjected to oxygen-glucose deprivation/reoxygenation, assessing cell viability, lipid peroxidation, ferroptosis-associated protein expression, and cytokine secretion following SS-31 intervention. Brain injury post-CA and resuscitation is significantly accompanied by ferroptosis of microglia. Treatment with SS-31 substantially improved survival rates, reduced neurological deficits, and lowered serum NSE and S100B levels. Mechanistically, SS-31 attenuated ferroptosis and promoted an anti-inflammatory shift in microglial polarization by enhancing GPX4 expression and decreasing iron content, oxidative stress, and pro-inflammatory cytokines. These effects were primarily mediated via the Sesn2 signaling pathway. SS-31 could effectively improve post-CA brain injury, in which the mechanism was potentially related to the inhibition of microglial ferroptosis and polarization through the regulation of Sesn2 signaling pathway.

Prolonged mechanical ventilation (PMV) is associated with increased morbidity and mortality among critically ill patients with ischemic stroke, yet data on its risk factors remain limited. This study aimed to identify independent predictors of PMV in this population. Ischemic stroke patients were identified from the Medical Information Mart for Intensive Care IV database. PMV was defined as mechanical ventilation lasting more than 14 days. Multivariable logistic regression was used to identify factors associated with PMV. Model performance was assessed using receiver operating characteristic curves, calibration plots, and decision curve analysis. A total of 756 ischemic stroke patients were included, of whom 111 (14.7 ​%) required PMV. In-hospital and one-year mortality rates in the PMV group were 27.0 ​% and 45.9 ​% respectively. Independent risk factors for PMV included BMI ≥33 ​kg/m² (OR 1.82, 95 ​% CI 1.10-3.02), COPD (OR 2.02, 95 ​% CI 1.25-3.24), pH ​≥ ​7.45 (OR 1.79, 95 ​% CI 1.12-2.86), respiratory rate ≥20 min^-1 (OR 2.39, 95 ​% CI 1.47-3.88), sepsis onset before D14 (OR 8.48, 95 ​% CI 1.75-41.06), tracheostomy (OR 7.38, 95 ​% CI 4.38-12.44), vasopressor (OR 2.19, 95 ​% CI 1.26-3.79) and pneumonia onset before D14 (OR 1.68, 95 ​% CI 1.01-2.79). These variables were incorporated into a nomogram, which demonstrated good discrimination (AUC 0.86, 95 ​% CI 0.83-0.89) and calibration (Hosmer-Lemeshow P ​= ​0.149). In conclusion, PMV in critically ill ischemic stroke patients is associated with COPD, sepsis, obesity, alkalosis, increased respiratory rate, tracheostomy, vasopressor use, and pneumonia. The predictive model incorporating these factors showed good diagnostic performance and may aid early risk stratification and management.

Delirium is a frequent complication among older adults and is linked to higher mortality, longer hospital stays, and greater healthcare expenditure. Although its clinical relevance is well recognized, routine diagnosis remains challenging because existing tools rely largely on the observation of fluctuating symptoms, which can easily be overlooked in daily practice. Electroencephalography (EEG) provides an objective measure of brain activity, and characteristic changes such as generalized slowing have been consistently described in patients with delirium. Despite these established findings, the conventional EEG setup is technically demanding and not well suited for repeated use in general hospital wards. In recent years, portable point-of-care (POC) EEG systems have been developed, allowing recordings with a limited number of electrodes at the bedside. Several clinical studies have reported that these devices are able to detect delirium with acceptable accuracy, while also offering practical advantages such as rapid deployment and use by non-specialist staff. Among the approaches investigated, the bispectral EEG (BSEEG) method has attracted particular attention. A higher BSEEG score has been shown to correlate with delirium severity and to predict adverse outcomes, including reduced survival, even in patients who did not present with overt clinical symptoms. Beyond the clinical setting, experimental work has applied EEG and BSEEG to rodent models of delirium induced by inflammation or surgery. These studies have highlighted associations between EEG slowing, microglial activation, and behavioral disturbances, suggesting that electrophysiological changes may provide a translational link between basic mechanisms and clinical phenomena. Preclinical data also indicate that BSEEG could serve as a quantitative tool for assessing treatment response in experimental models. Taken together, these findings support the potential of simplified EEG platforms to complement current diagnostic strategies. If further validated in larger, real-world cohorts, bedside EEG may become a practical adjunct for the early recognition of delirium and the monitoring of disease progression, with implications for both patient outcomes and mechanistic research.