Neurotherapeutics最新文献

Racemic (R,S)-ketamine exerts rapid antidepressant effects, and growing evidence suggests its R-isomer may offer sustained efficacy with fewer side effects. However, the neurobiological mechanisms underlying (R)-ketamine's action in the human brain are largely unknown. To address this, we acquired resting-state fMRI data from 32 healthy volunteers 24 ​h before and after intranasal administration of (R)-ketamine (n ​= ​24) or placebo (n ​= ​8). We primarily assessed changes in long-range functional synchrony using degree centrality (DC) and elucidated the sources of these changes with functional connectivity (FC) analysis. (R)-ketamine significantly decreased DC in a key cognitive-motor integration hub: the supplementary motor area/middle cingulate cortex (SMA/MCC, cluster-corrected P ​< ​0.05). Critically, the reduction of DC was absent under the placebo condition, yielding a significant group-by-time interaction (P ​= ​0.01). The reduction in long-range synchrony of the SMA/MCC was primarily driven by attenuated FC with both the dorsal medial prefrontal cortex/dorsal anterior cingulate cortex (dMPFC/dACC) and the cerebellum, and was spatially correlated with serotonin, norepinephrine, and acetylcholine neurotransmitter profiles. More importantly, the clinical relevance of the neuroimaging phenotypes was established in an independent Major Depressive Disorder (MDD) cohort, where FC between the SMA/MCC and dMPFC/dACC significantly correlated with depressive symptom severity (HAMD score, P ​= ​0.019). This study provides novel, system-level evidence that intranasal (R)-ketamine modulates specific human brain networks by attenuating long-range synchrony in the SMA/MCC. The link between the neuroimaging phenotype, depression-relevant neurotransmitter profiles, and clinical symptom severity may offer a plausible therapeutic mechanism of (R)-ketamine.

Neuropsychiatric symptoms (NPS) are among the most distressing and functionally disruptive features of Alzheimer's disease (AD), affecting the vast majority of individuals across the disease continuum. These symptoms, ranging from apathy and depression to agitation and psychosis, not only worsen quality of life but also predict faster decline, earlier institutionalization, and heightened caregiver burden. Yet, despite their clinical significance, NPS remain under-recognized and undertreated. This review synthesizes current understanding of the biological underpinnings of NPS in AD, highlighting network-level dysfunction, neurotransmitter imbalances, neuroinflammation, and emerging roles for tau pathology and circadian disruption. We critically examine current treatment paradigms, noting that pharmacologic interventions offer benefit but often carry significant risks. In contrast, non-pharmacological approaches, particularly those that integrate caregiver training, environmental design, and sensory engagement, hold promise but are inconsistently applied in routine care. Emerging innovations, including neuromodulation, repurposed agents (e.g., beta-blockers, cannabinoids), and digital therapeutics such as virtual reality and AI-enabled monitoring tools, offer new therapeutic avenues. We call for a paradigm shift toward person-centered, mechanistically-informed care that aligns intervention strategies with biological drivers of NPS. Future progress hinges on inclusive clinical trials, implementation of first-line behavioral strategies, and development of biomarker-guided, precision approaches to symptom management. Effective care for NPS in AD demands integration, not substitution, of pharmacologic and non-pharmacologic strategies, grounded in a deeper understanding of both disease biology and lived patient experience.

Ischemic retinal damage is the most common cause of severe vision impairment and blindness. Anti-vascular endothelial growth factor (anti-VEGF) agents have transformed the treatment of retinal ischemic disorders and have become the cornerstone therapy for these conditions. Nonetheless, the risk for systemic and ocular adverse effects necessitates careful consideration. Meanwhile, the therapeutic potential of natural compounds for ischemic retinal injury is increasingly attracting attention. In this study, piperine (PIP), a natural compound derived from pepper, was found to reduce apoptosis by reducing the severity of retinal and optic nerve ischemic damage. However, the precise pharmacological mechanisms of PIP are yet to be fully elucidated. Molecular docking (MD) studies, MD simulations, and surface plasmon resonance experiments were conducted to determine the molecular targets of PIP. Our data revealed that PIP can bind to apurinic/apyrimidinic endonuclease 1 (APE1), thereby inhibiting apoptosis by decreasing the expression of caspase-9 and caspase-3 and regulating the mitochondrial pathway. In summary, PIP may directly targets the APE1 protein and further regulates the caspase-9/caspase-3 axis to provide neuroprotection against ischemic retinal injury.

There is an unmet need in the treatment of traumatic brain injury (TBI), a leading cause of death and disability. Colony stimulating factor 1 receptor (CSF1R) and interleukin 1 receptor type 1 (IL1R1) are critical regulators of TBI-associated neuroinflammation. This study tested the hypothesis that early administration of CSF1R inhibitor PLX3397 plus IL1R1 inhibitor Anakinra alleviates TBI pathogenesis. Adult C57BL/6 mice were subjected to experimental TBI and treated with PLX3397 plus Anakinra, PLX3397 or Anakinra alone, or vehicle for up to five days post injury (5 dpi). Neurological deficits were attenuated by PLX3397 plus Anakinra in male and female mice. Combination therapy, as opposed to monotherapy, also reduced structural brain damage; however, this effect was observed exclusively in male mice. Bulk RNA-sequencing analysis of differentially expressed genes (DEGs) and gene set enrichment analysis (GSEA) revealed anti-neuroinflammatory effects in male mice treated with PLX3397 plus Anakinra, which exceeded the summed effects of monotherapies. Key DEGs included pro-neuroinflammatory markers such as Cd68 and Spp1/osteopontin, as well as genes associated with type I and II interferon responses. Immunofluorescence staining confirmed that PLX3397 plus Anakinra was more effective than monotherapy in attenuating CD68⁺ macrophages/microglia, CD45⁺/CD68^- leukocytes, and osteopontin. Again, these effects exceeded the summed effects of monotherapy. The findings demonstrate beneficial synergistic effects of FDA-approved CSF1R and IL1R1 inhibitors and offer novel insights into the mechanisms of early TBI pathogenesis and therapy in a clinically relevant model.

Severe, cystic white matter injury (WMI) in preterm infants is associated with neurodevelopmental impairment. Strikingly, it often develops weeks after birth. In the present study we tested the hypothesis that necrotic programmed cell death, necroptosis, may be a key mediator of severe WMI, using the specific inhibitor necrostatin-1s (Nec-1s). Chronically instrumented preterm fetal sheep (0.7 gestation) received 25 ​min of hypoxia-ischaemia induced by complete umbilical cord occlusion (UCO) or sham-UCO (controls, n ​= ​9), followed by intracerebroventricular infusion of Necrostatin-1s at 3, 8 and 13 days after UCO (UCO-Nec-1s, n ​= ​8) or vehicle (UCO-vehicle, n ​= ​9). Histology was obtained at 21 days after UCO. UCO-vehicle was associated with a spectrum of brain injury including diffuse WMI, and in 7/9 fetuses, generalised white matter atrophy, ventriculomegaly and/or temporal lobe cystic lesions. Necrostatin-1s infusion was associated with less severe WMI in the temporal lobe (1/8, p ​= ​0.041), with reduced atrophy, increased density of mature oligodendrocyte cells, myelin area fraction, and reduced microgliosis but increased numbers of apoptotic cells. Interestingly, diffuse white matter injury in the parietal tracts was not affected. This study suggests that delayed, severe white matter injury after acute hypoxia-ischaemia is mediated by slowly evolving necroptosis and neuroinflammation. We speculate that Nec-1s shifts the dominant cell death pathway from necrosis toward apoptosis, allowing reduced inflammation and so preserving oligodendrocyte populations and myelination in the temporal lobe. These results suggest that necroptosis is a promising therapeutic target to mitigate severe white matter injury.

Guillain-Barré syndrome (GBS), an acute autoimmune peripheral neuritis, remains a clinical challenge due to limited therapeutic efficacy and heterogeneous patient responses. The present study investigated salidroside (SAL), a bioactive phenylethanoid glycoside derived from Rhodiola rosea, for its dual anti-inflammatory and neuroprotective properties using experimental autoimmune neuritis (EAN), a validated GBS model. Integrated network pharmacology and molecular docking analyses identified PI3K/AKT signaling as the principal mechanistic target of SAL. In vivo administration of SAL (100 ​mg/kg/day, intragastric) significantly reduced neurological deficits, alleviated histopathological damage in sciatic nerves, and restored Th1/Th17-Treg immune balance in EAN rats. Mechanistic analysis demonstrated that SAL inhibited NF-κB activation through inhibition of IκBα degradation and p65 nuclear translocation, leading to downregulation of pro-inflammatory cytokines (TNF-α). Concurrently, SAL promoted macrophage polarization from the pro-inflammatory M1 (CD86⁺) to anti-inflammatory M2 (CD206⁺) phenotypes. The findings indicate that SAL mitigates EAN through a dual mechanism involving suppression of NF-κB-mediated neuroinflammation and immunomodulation via macrophage phenotype remodeling. The results further establish the PI3K/AKT pathway as a pharmacologically tractable target in autoimmune neuropathies and provide mechanistic evidence supporting SAL as a multi-target immunomodulatory candidate for GBS therapy.

Despite effective antiretroviral therapy, many people living with HIV (PLH) experience cognitive impairments, particularly in executive function and working memory. These deficits have been linked to dysregulation of brain circuits involving the neuropeptide N-acetyl-aspartyl glutamate (NAAG), which is catabolized by the enzyme glutamate carboxypeptidase II (GCPII). Inhibiting GCPII elevates brain NAAG levels and improves cognition in preclinical models. In prior magnetic resonance spectroscopy (MRS) studies, we demonstrated that higher brain NAAG levels in PLH correlate with better cognitive performance, highlighting NAAG as a potential biomarker and GCPII as a potential therapeutic target. In this study, we used EcoHIV-infected mice to model HIV-associated neurocognitive disorders and evaluated the therapeutic potential of the selective GCPII inhibitor 2-PMPA. We found that 2-PMPA treatment increased cerebrospinal fluid (CSF) NAAG levels by 800 ​% and reversed EcoHIV-induced deficits in social interaction, recognition memory, and fear conditioning, without affecting general locomotion or anxiety-like behavior. Furthermore, 2-PMPA restored synaptic density and preserved dendritic structure in EcoHIV-infected mice, indicating a neuroprotective effect. These findings provide strong evidence that GCPII inhibition represents a viable therapeutic strategy for HIV-associated cognitive dysfunction by elevating NAAG and protecting neural circuits critical for cognition.

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.