Neurotherapeutics最新文献

Interventional trials with high-density lipoprotein cholesterol (HDL-C)-raising drugs have generally failed to demonstrate a beneficial effect on cardiovascular outcomes, although low HDL-C levels confer the risk of cerebrocardiovascular diseases. Previous experimental studies indicate that HDL-C promotes angiogenesis/arteriogenesis. Therefore, we aimed to clinically investigate whether high blood HDL-C levels could clinically predict cerebral hemodynamic improvements in patients with asymptomatic carotid artery stenosis/occlusion showing cerebral hypoperfusion. This longitudinal retrospective observational study included a total of 66 hemispheres governed by asymptomatic carotid artery stenosis/occlusion in patients who underwent 2-time multi-parametric ¹⁵O-gas positron emission tomography (PET). The longitudinal changes of multiple parameters, including cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen, and oxygen extraction fraction (OEF) values were scrutinized between patients with high and low baseline blood HDL-C levels. The cerebral hemodynamic parameters were normalized to the bilateral cerebellum. The median interval between PET examinations was 212.0 and 219.0 days for patients with low and high HDL-C levels, respectively (p = 0.91). A high blood HDL-C level was an independent predictor of increasing CBF (β [mean difference]: 0.035, 95 % confidence interval [CI]: 0.010-0.060), and CBV (β: 0.26, 95 % CI: 0.023-0.50), and decreasing OEF (β: -0.041, 95 % CI: -0.077 to -0.006) in the anterior circulation territory. A high blood HDL-C level was clinically an independent predictor of cerebral hemodynamic improvement. HDL-C could be an important therapeutic target for ischemic stroke prevention by improving cerebral hemodynamic parameters presumably via angiogenesis and arteriogenesis especially in patients showing cerebral hypoperfusion.

Chronic neuroinflammation and accumulation of phosphorylated Tau (pTau) are hallmark features of several neurodegenerative diseases and are also observed in some individuals who have sustained traumatic brain injury (TBI). Notably, more than 70 % of patients presenting to emergency departments with mild TBI (Glasgow Coma Score of 13-15) exhibit neuropathological alterations despite a normal sensorium, and up to half experience prolonged post-injury symptoms. Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a serine/threonine protein kinase that contributes to tau phosphorylation and regulates immune responses. Inhibition of DYRK1A may therefore attenuate both tau pathology and neuroinflammation following injury. Transgenic mice expressing human Tau (hTau) were subjected to repetitive head injury (RHI) over a 3-month period and treated with either vehicle or SM07883, a potent, brain-penetrant DYRK1A inhibitor. Behavioral performance was evaluated using the Rotarod and Barnes Maze tests, and neuropathological assessments were performed six months after the first injury. SM07883 treatment restored locomotor performance in injured animals and ameliorated age-related motor decline in sham-treated mice. These behavioral improvements were accompanied by significant reductions in RHI-induced pTau accumulation within the midbrain and brainstem, along with decreased astroglial and microglial activation in the corpus callosum, brainstem, and cortical regions beneath the injury site. Collectively, these findings demonstrate that DYRK1A inhibition mitigates tau pathology and chronic neuroinflammation following repetitive injury, supporting DYRK1A as a promising therapeutic target for the long-term neurological consequences of TBI.

Migraine is a highly prevalent and severe neurological condition characterized by disabling headache attacks accompanied by other neurological symptoms. Its pathophysiology involves activation of the trigeminovascular system, cortical spreading depolarization, and dysregulation of brainstem and diencephalic nuclei. Although most studies have focussed mainly on the role of neurons, there is mounting evidence that non-neuronal cells could also participate in migraine pathophysiology and could represent targets for current and future therapies. As reviewed in this manuscript, preclinical evidence links astrocytes, microglia and satellite glial cells with cortical spreading depolarization, trigeminovascular activation, and the development of orofacial allodynia, processes that are central to migraine. These cells could be potential targets for calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) therapies. Schwann cells have been less studied, but existing data suggest they could be targeted by anti-CGRP treatments. Macrophages respond to CGRP, contribute to cortical spreading depolarization and orofacial mechanical allodynia, and may be modulated to enhance an anti-inflammatory environment. Mast cells express receptors for CGRP and other relevant neuropeptides, and have gained attention through the development of monoclonal antibodies against their protease-activated receptor 2 (PAR2), currently in phase 2 clinical trials. Further studies are needed to better elucidate the molecular complexity of non-neuronal cells and their role in migraine, but future approaches using adeno-associated viral vectors, nanoparticles, and cell replacement strategies could enable the development of innovative anti-migraine therapies.

Schizophrenia is a chronic, disabling and potentially fatal psychiatric syndrome characterized by three primary symptom domains: positive, negative, and cognitive symptoms, for which current dopamine D₂ receptor antagonists provide only partial benefit and are limited by significant side effects. Muscarinic acetylcholine receptors (mAChRs), broadly expressed across cortical, striatal, and midbrain circuits, have emerged as promising targets for next-generation therapies. Among these, M₁ and M₄ receptor subtypes play key roles in regulating glutamatergic and dopaminergic transmission. Clinical studies with xanomeline, an orthosteric agonist with functional preference for M₁ and M₄ receptors, provided the first proof that mAChR agonists can reduce psychotic symptoms. Reformulation of xanomeline with trospium chloride, a peripherally-restricted mAChR antagonist, improved its tolerability and allowed confirmation of its efficacy in large Phase 2 and 3 trials. Current and future efforts are now focused on developing more selective orthosteric and allosteric mAChR agonists and more precisely characterizing their therapeutic activity (efficacy and safety) in clinical trials. These advances highlight mAChR pharmacology as a novel and clinically validated strategy that extends beyond dopamine D₂ receptor antagonism to potentially address the full spectrum of schizophrenia symptoms.

Cathodal transcranial direct current stimulation (C-tDCS) is a potential neuroprotective method in the hyperacute phase of ischemic stroke. We aimed to assess safety, tolerability, feasibility, and potential efficacy of C-tDCS in stroke patients with salvageable penumbra. DICAST-SF was a double-blind, randomized, sham-controlled (3 active: 1 sham), 3 + 3 dose-escalation trial. Inclusion criteria were stroke due to occlusion of the internal carotid or middle cerebral artery, last known well time within 24 h, substantial penumbra on CT perfusion, and ineligibility for mechanical thrombectomy. We applied C-tDCS at six dose tiers over the affected primary motor cortex. The primary safety outcome was the symptomatic intracranial hemorrhage (SICH) rate at 24 h post-stimulation. Secondary outcomes included the rates of asymptomatic intracranial hemorrhage (AICH), early neurological deterioration, serious adverse events, and 90-day mortality. Tolerability was assessed by completion rate and questionnaires. Feasibility threshold was defined as median randomization-to-C-tDCS start time within 10 min in the last ten patients. Twenty five patients were enrolled (19 active, 6 sham), mean age 81 (SD 12) years, 16 women, median NIHSS 8 (IQR 6-16). Ten active and 4 sham patients were treated with thrombolysis. No SICH occurred. Three AICH (2 post-thrombolysis) occurred in the active arm. Rates of early deterioration, serious adverse events, and mortality (4 active vs. 2 sham) were comparable. C-tDCS was well tolerated and feasible, median randomization-to-C-tDCS start time was 8 (7-9) min. C-tDCS in hyperacute stroke was safe, well tolerated, and feasible. Findings support further evaluation in larger efficacy trials. TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04801446.

Memory impairment is a common comorbidity of chronic pain that significantly compromises patients' quality of life, yet the underlying neuronal circuit mechanisms remain poorly understood. Here, we employed a spared nerve injury (SNI) mouse model of chronic neuropathic pain and evaluated short-term memory performance using a novel object recognition test (NORT). Mice exhibited mechanical allodynia and object recognition memory (ORM) deficits 21 days following SNI surgery. Functional Magnetic Resonance Imaging (fMRI) analyses revealed a reduction in functional connectivity between the prelimbic cortex (PrL) and the lateral entorhinal cortex (LEC) in SNI mice. Viral tracing confirmed a direct monosynaptic anatomical projection from the PrL to the LEC, originating primarily from PrL layer 5 neurons. c-Fos immunostaining and in vivo calcium fiber photometry further demonstrated that both the PrL and LEC neurons were activated in response to novel object recognition, whereas these neuronal responses were significantly attenuated in SNI mice. Importantly, selective chemogenetic and optogenetic activation of the PrL-LEC pathway improved memory impairment in SNI mice without affecting pain sensitivity or locomotor activity. Chemogenetic inhibition of this pathway impaired ORM performance in normal mice. Our findings underscore the important role of PrL-LEC pathway hypoactivity in mediating short-term memory deficits associated with chronic pain and suggest this circuit as a promising therapeutic target for pain-related cognitive dysfunction.

Recent clinical breakthroughs hold great promise for the application of psilocybin in the treatments of psychological disorders, such as depression, addiction, and obsessive-compulsive disorder. Psilocybin is a psychedelic whose metabolite, psilocin, is a 5-HT_2A receptor agonist. Nevertheless, the underlying mechanisms for the effects of psilocybin on the brain are not fully illustrated, and cell type-specific and circuit effects of psilocybin are not fully understood. Here, we combined single-nucleus RNA-seq with functional assays to study the long-term effects of psilocybin on the orbitofrontal cortex (OFC) of male mouse, a brain region vulnerable to psychological disorders such as depression. We found that a single dose of psilocybin induced long-term genetic and functional changes in neurons of the OFC, and the layer 5 pyramidal neurons showed the most significant changes. The layer 5 pyramidal neurons in the OFC showed reduced expressions of glutamate receptors and the gene expressions of multiple intercellular signaling pathways involved in the excitatory synapse formation and maintenance after psilocybin injection, which was consistent with the decreased excitatory synaptic transmission of these neurons. Meanwhile, both Parvalbumin- and Somatostatin-positive inhibitory neurons of the OFC showed meager changes after psilocybin injection. Furthermore, knockdown of 5-HT_2A receptor in the layer 5 pyramidal neurons but not the Parvalbumin-positive inhibitory neurons abated psilocybin-induced functional changes and the anti-depressant effect. Together, these results showed the cell type-specific mechanisms of psilocybin and shed light on the brain region difference in the effect of psychedelics.

Trigeminal nerve stimulation (TNS) is a minimal-risk, noninvasive neuromodulation method with growing evidence of efficacy across psychiatric conditions. However, its safety and potential effects in autism spectrum disorder (ASD) remain underexplored. This exploratory pilot study aimed primarily to evaluate the safety and tolerability, and secondarily to explore changes in ASD-related symptoms - including impairments in social communication and reciprocity, attention, executive functioning, emotional regulation, sleep, and sensory processing - in children with ASD, and to examine associated changes using quantitative electroencephalography (qEEG). This double-blind, sham-controlled, randomized exploratory pilot trial enrolled 29 children aged 7-12 years with ASD. The participants were randomized to receive 28 nightly sessions of active or sham TNS over 4 weeks. At baseline and week 4, we assessed safety, clinical outcomes and Clinical Global Impression scales, in addition to analyzing qEEG band power. No serious adverse events were observed, and TNS was well tolerated. Exploratory analyses showed nominal between-group differences (unadjusted) favoring the TNS group in maladaptive behavior (Vineland-II: 1.38 vs 0.08; p = .017) and social reciprocity (Social Responsiveness Scale-2: 12.07 vs -1.43; p = .025). Exploratory qEEG analyses revealed decreased gamma/high-frequency and increased alpha power in the left frontal and parietal regions, changes that significantly correlated with improvements in social (r = -0.917; p = .001) and overall (r = -0.680; p = .030) functioning. TNS was safe and showed preliminary evidence of potential benefits in improving behavioral and social functioning in children with ASD. Larger trials are required to confirm these findings. Clinical trial registration information: http://clinicaltrials.gov/; NCT06233279.

We aim to evaluate sleep disruption in people with multiple sclerosis (MS) compared to an age- and gender-matched control cohort using patient-reported outcome measures and formal polysomnography (PSG) scoring, and testing the effect of Nabiximols on these measures in people with MS. We enrolled adult individuals with MS who were eligible to receive nabiximols. Clinical variables and self-reported items like Pittsburgh Sleep Quality Index (PSQI) score were collected. Individuals underwent two full-night PSG recordings: baseline and after a 6-week nabiximols trial. Additionally, 24 healthy individuals (18 females; mean age:55.7 ± 9.5 years) were recruited as control cohort. Linear mixed-effects models (LMMs) using clinical and PSG parameters were used. Our cohort of 19 people with MS (16 females; mean age of 50.8 ± 10.2 years) with elevated PSQI (11.7 ± 2.8) exhibited: reduced sleep efficiency (SE)[P < 0.001,q-value = 0.003], reduced total sleep time (TST)[P = 0.0021,q-value = 0.005], higher number of awakenings [P < 0.001,q-value = 0.003], increased arousal-index (AI) [P < 0.001,q-value = 0.003], a greater periodic limb movement index (PLMI) [P < 0.001,q-value = 0.003] and a reduced proportion of REM [P < 0.001,q-value = 0.003] compared with the controls. The 6-weeks nabiximols trial resulted in a significant improvement in the PSQI [β 95%CI = -1.28 (-1.67, -0.88)] and in the following PSG measures: SE [β 95%CI = 1.57 (1.18, 1.95)], TST [β 95%CI = 0.93 (0.46, 1.40)], AI [β 95%CI = -1.41 (-1.79, -1.30)], PLMI [β 95%CI = -1.73 (-2.03, -1.43)] and REM sleep [β 95%CI = 1.44 (1.00, 1.87)]. Our prospective study reported a significant sleep disruption in MS and a great improvement in sleep parameters following a 6-week trial of Nabiximols, as indicated by LMMs using PSQI score and PSG measures. We suggest broadening the therapeutic indications of nabiximols to also include individuals with MS who experience significant sleep disruption.

Efgartigimod is an established therapy for acetylcholine receptor antibody-positive generalized myasthenia gravis, yet real-world data on long-term overall responsiveness, response patterns, steroid-sparing effects, bridging therapy use, and predictors of benefit remain limited. In this multicenter retrospective study, we evaluated 46 patients treated across seven tertiary centers between April 2022 and March 2025, collecting demographic, clinical, therapeutic, and outcome data. Patients received 193 treatment cycles (mean 4.3 per patient) with a mean inter-cycle interval of 9.8 weeks. Following the first cycle, 86.9 % achieved a ≥2-point improvement in the Myasthenia Gravis Activities of Daily Living scale and 43.5 % reached minimal symptom expression (MSE); overall, 52.2 % achieved MSE at least once during follow-up. Nonetheless, 35.9 % discontinued efgartigimod due to insufficient efficacy, underscoring heterogeneous and often non-durable responses. Among 29 patients on prednisone, 58.6 % achieved a significant dose reduction (30.9-16.8 mg/day, p = 0.001), with shorter disease duration predicting successful tapering. Bridging therapy was successful in 5 patients, particularly those receiving azathioprine or mycophenolate (p = 0.040), supporting its utility during transitions to slower-acting immunosuppressants. Adverse events occurred in 21.7 % of patients, were generally mild, and led to discontinuation in only one case. Overall, efgartigimod was effective and well tolerated, but treatment responses varied, and cycle-based regimens frequently failed to sustain benefit. The observed steroid-sparing effect and predictors of response highlight the need for personalized treatment strategies and prospective studies to refine long-term use and optimize patient selection.