Neurotherapeutics最新文献

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.

Diabetes increases post-stroke mortality and cognitive impairment (PCSI). We previously demonstrated that iron chelation during the subacute phase enhances cognitive outcomes after stroke in experimental diabetes. Here, we hypothesized that inhibition of ferroptosis, an iron-induced form of cell death, in the post-stroke period would prevent PSCI in diabetic animals. Diabetic male rats underwent sham or 60-min middle cerebral artery occlusion surgery. On Day 3 post-stroke, animals meeting the inclusion criteria (adhesive removal time >35 ​s on Day 3 and either a modified Bederson score ≤6 on Day 0 or weight loss >10 ​% on Day 1) were randomized to ferroptosis inhibitor UAMC-3203 (2 ​mg/kg) or vehicle treatment for 2 weeks (n ​= ​8-12/group). Sensorimotor/cognitive outcomes were monitored for 8 weeks. As confirmed by MRI, the inclusion criteria predicted successful stroke surgery for over 95 ​% of the animals. Preset inclusion criteria ensured that comparable deficits were present at randomization. There were significant acute neurological deficits. Animals developed episodic and spatial memory deficits after stroke, and UAMC-3203 treatment prevented this decline. All animals showed anxiety-like behavior even at baseline, and this behavior was reversed only in the stroke treatment group. Interestingly, step-through latency in the passive avoidance test showed that stroke does not affect learning in vehicle-treated diabetic animals; however, the latency was lower in the stroke treatment group, suggesting inhibition of ferroptosis impairs aversive learning after stroke. At the molecular level, lipid peroxidation (4-HNE levels) was amplified after stroke, and UAMC-3203 prevented this increase and preserved antioxidant GPX-4 protein levels. Our findings provide evidence that ferroptosis contributes to the development of progressive cognitive decline in memory functions after stroke in diabetes. The prevention of ferroptosis with a third-generation ferroptosis inhibitor is beneficial; however, the adverse effect of treatment on aversive learning warrants further investigation.

Parkinson's disease (PD) presents with both motor and non-motor symptoms, including depression and anxiety, which often precede motor onset, yet the mechanisms linking these affective symptoms to PD pathology remain unclear. In this study, we investigated the bidirectional relationship between depression/anxiety behaviors and α-synuclein (α-syn) propagation using A53T α-syn transgenic mice subjected to chronic restraint stress (CRS) and/or intrastriatal injection of α-syn preformed fibrils (PFFs). Behavioral testing and immunohistochemical analyses revealed that CRS enhanced PFF-induced α-syn propagation and exacerbated depression/anxiety-like behaviors, while α-syn propagation was associated with aggravated CRS-induced behavioral deficits, indicating a potential reciprocal association that could contribute to accelerating PD progression. This interaction was mediated by the neuronal activity marker c-Fos. Pharmacological inhibition of c-Fos with T5224 mitigated both behavioral and pathological changes, and mGluR5 activation was found to partially contribute to c-Fos induction and α-syn spread. Together, these findings highlight a feedback interaction between affective symptoms and α-syn pathology in PD, mediated in part by neuronal activity-dependent mechanisms involving c-Fos and mGluR5, and suggest that early interventions targeting both neuronal activity and α-syn propagation may slow PD progression and improve patient quality of life.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurons (MNs) degenerative disease. Despite advancements in understanding ALS pathogenesis, drug development lags far behind. The reduced secretion of phosphoglycerate kinase 1 (Pgk1) by NogoA-overexpressing muscle cells inhibits neurite outgrowth of MNs (NOMNs). However, administration of extracellular Pgk1 (ePgk1) reduces phospho-Cofilin (p-Cofilin), a growth cone collapse marker, and mitigates MN degeneration. This improves NOMNs in NSC34 neural cells and locomotion in SOD1-G93A ALS-mice by suppressing the p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 signaling pathway. Here, we identified two Pgk1-based 16-amino acid (aa) short peptides, FD-1 and FD-2, with neuroprotective effects equivalent to those of full-length ePgk1. Administration of FD-1 or FD-2 (FD-1/-2) reduced p-Cofilin and promoted NOMNs in NSC34 ​cells cultured in conditioned medium obtained from NogoA-overexpressing muscle cells. Furthermore, we found that exogenous addition of FD-1/-2 to the culture medium attenuated the accumulation of phospho-Tau-S396 and the cytoplasmic mislocalization of transactive response DNA binding protein of 43 ​kDa (TDP-43) in oxidative-stressed ALS-like SOD1-G93A NSC34 ​cells. In FD-1/-2-injected zebrafish embryos, we observed increased caudal primary MNs branching. In C9orf72-knockdown and hTDP-43-G348C mRNA overexpressing zebrafish embryos injected with FD-1/-2, axonal growth and motor function were rescued. Moreover, intravenous injection of FD-1/-2 in SOD1-G93A ALS-mice delayed denervation of neuromuscular junction, preserved cell bodies of MNs in the ventral horn of spinal cord, increased grip strength, improved locomotion and prolonged survival. Therefore, both 16-aa short FD peptides are functionally equivalent to full-length 417-aa ePgk1 and thus promising therapeutic short peptides for the treatment of ALS.

Short-chain fatty acids such as butyrate (key signaling molecules that influence the gut-brain axis and modulate inflammatory, mitochondrial, and transcriptional regulatory processes) are attracting interest as potential treatments for neurodegenerative disorders such as Parkinson's disease. Oral butyrate supplementation in the form of sodium butyrate suffers from limitations, however, as butyrate is rapidly metabolized by colonocytes, resulting in low plasma and brain concentrations. The butyrate prodrug tributyrin, naturally present in butter, is a neutral short-chain fatty acid triglyceride likely to overcome the pharmacokinetic drawbacks of butyrate. Despite these pharmacokinetic advantages, no clinical studies to date have assessed the safety, tolerability, and target engagement of tributyrin as a postbiotic treatment in the setting of Parkinson's disease. Tributyrin's safety profile and potential biomechanistic effects were thus investigated in the setting of Parkinson's disease via an open-label target engagement study. Fourteen individuals with Parkinson's disease and three normal controls completed a 30-day (±7 days) intervention of dietary tributyrin supplementation (500 ​mg taken orally three times daily), demonstrating a reassuring safety profile with high rates of adherence. Ten subjects completed [¹¹C]butyrate PET imaging before and after the intervention to assess for treatment-related changes in brain, liver, heart, and gastrointestinal uptake of butyrate, confirming target engagement (i.e., organ-specific changes in butyrate availability). Systemic anti-inflammatory effects were also observed. Exploratory cognitive, motor, and neurobehavioral clinical testing was conducted before and after the supplementation period, identifying associated improvements in cognitive and motor features of Parkinson's disease. Given these findings, tributyrin warrants further investigation via larger, placebo-controlled trials as a potential complementary therapy for Parkinson's disease.