Neurotherapeutics最新文献

Alzheimer's disease (AD) presents significant challenges in drug discovery and development due to its complex and poorly understood pathology and etiology. Digital twins (DTs) are recently developed virtual real-time representations of physical entities that enable rapid assessment of the bidirectional interaction between the virtual and physical domains. With recent advances in artificial intelligence (AI) and the growing accumulation of multi-omics and clinical data, application of DTs in healthcare is gaining traction. Digital twin technology, in the form of multiscale virtual models of patients or organ systems, can track health status in real time with continuous feedback, thereby driving model updates that enhance clinical decision-making. Here, we posit an additional role for DTs in drug discovery, with particular utility for complex diseases like AD. In this review, we discuss salient challenges in AD drug development, including complex disease pathology and comorbidities, difficulty in early diagnosis, and the current high failure rate of clinical trials. We also review DTs and discuss potential applications for predicting AD progression, discovering biomarkers, identifying new drug targets and opportunities for drug repurposing, facilitating clinical trials, and advancing precision medicine. Despite significant hurdles in this area, such as integration and standardization of dynamic medical data and issues of data security and privacy, DTs represent a promising approach for revolutionizing drug discovery in AD.

Predicting long-term prognosis and choosing the appropriate therapeutic approach in patients with Multiple Sclerosis (MS) at the time of diagnosis is crucial in view of a personalized medicine. We investigated the impact of early therapeutic response on the 5-year prognosis of patients with relapsing-remitting MS (RRMS). We recruited patients from MSBase Registry covering the period between 1996 and 2022. All patients were diagnosed with RRMS and actively followed-up for at least 5 years to explore the following outcomes: clinical relapses, confirmed disability worsening (CDW) and improvement (CDI), EDSS 3.0, EDSS 6.0, conversion to secondary progressive MS (SPMS), new MRI lesions, Progression Independent of Relapse Activity (PIRA). Predictors included demographic, clinical and radiological data, and sub-optimal response (SR) within the first year of treatment. Female sex (HR 1.27; 95 ​% CI 1.16-1.40) and EDSS at baseline (HR 1.19; 95 ​% CI 1.15-1.24) were independent risk factors for the occurrence of relapses during the first 5 years after diagnosis, while high-efficacy treatment (HR 0.78; 95 ​% CI 0.67-0.91) and age at diagnosis (HR 0.83; 95 ​% CI 0.79-0.86) significantly reduced the risk. SR predicted clinical relapses (HR ​= ​3.84; 95 ​% CI 3.51-4.19), CDW (HR ​= ​1.74; 95 ​% CI 1.56-1.93), EDSS 3.0 (HR ​= ​3.01; 95 ​% CI 2.58-3.51), EDSS 6.0 (HR ​= ​1.77; 95 ​% CI 1.43-2.20) and new brain (HR ​= ​2.33; 95 ​% CI 2.04-2.66) and spinal (HR 1.65; 95 ​% CI 1.29-2.09) MRI lesions. This study highlights the importance of selecting the appropriate DMT for each patient soon after MS diagnosis, also providing clinicians with a practical tool able to calculate personalized risk estimates for different outcomes.

The complexity and expansive nature of thalamic research has led to numerous interventions for varied disease states. At the same time, this complexity along with siloed areas of study can hinder a comprehensive understanding. The goal of this paper is to give the reader a broader and more detailed perspective on the thalamus. In order to accomplish this goal, the paper begins with a summary of the function, electrophysiology, and anatomy of the normal thalamus. With this foundation, thalamic involvement in neurological diseases is discussed with a focus on epilepsy. Therapeutic interventions in the thalamus for epilepsy as well as movement disorders, psychiatric conditions and disorders of consciousness are described. Lastly limitations in the field and future models of data sharing and cooperation are explored.

Neuromodulation therapy using chemogenetic stimulation has shown potential in enhancing motor recovery and neuroregeneration following spinal cord injury (SCI). These therapeutic benefits are hypothesized to result from the promotion of neuroplasticity, particularly when administered during the acute phase of injury. In this study, we investigated the effects of chemogenetic stimulation using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in conjunction with clozapine, a ligand for receptor activation. DREADDs enable targeted, reversible neuromodulation, facilitating the histological characterization of engineered neurons. We utilized these receptors to modulate G-protein-coupled receptor (GPCR) signaling pathways, leading to the activation or inhibition of intracellular signaling. The objective was to determine whether the administration of DREADDs and clozapine (0.1 ​mg/kg) could enhance motor function and neuronal recovery, particularly when applied during the acute phase of SCI. Weekly behavioral assessments demonstrated significant improvements in motor skills and neuronal regeneration in treated animals compared to controls, with the most pronounced effects observed when stimulation was initiated early after injury. These enhancements in neuroplasticity were reflected in improved ladder rung test scores and Basso, Beattie, and Bresnahan (BBB) scale results in DREADDs-treated rats. Histological analyses, including immunohistochemistry (IHC) staining, Western blotting, and quantitative reverse transcription PCR (qRT-PCR), confirmed that the treatment group exhibited a higher density of neurons, increased signaling protein expression, and reduced inflammatory markers. These findings suggest that chemogenetic stimulation, particularly when administered during the acute phase, effectively promotes neuroregeneration and motor recovery. Future research should focus on assessing the long-term safety and efficacy of chemogenetic virus injection and clozapine administration, with an emphasis on the timing of intervention.

Dystonia is the third most common movement disorder and an incapacitating co-morbidity in a variety of neurologic conditions. Dystonia can be caused by genetic, degenerative, idiopathic, and acquired etiologies, which are hypothesized to converge on a "dystonia network" consisting of the basal ganglia, thalamus, cerebellum, and cerebral cortex. In acquired dystonia, focal lesions to subcortical network regions lead to dystonia that can be difficult to manage with canonical treatments, including deep brain stimulation (DBS). While studies in animal models have begun to parse the contribution of individual nodes in the dystonia network, how acquired injury to the cerebellar outflow tracts instigates dystonia; and how network modulation interacts with symptom latency remain unexplored questions. Here, we present an electrolytic lesioning paradigm that bilaterally targets the cerebellar outflow tracts. We found that lesioning these tracts, at the junction of the superior cerebellar peduncles and the medial and intermediate cerebellar nuclei, resulted in transient, acute, and severe dystonia with immobility and fixed posturing similar to status dystonicus. We observed a rapid reduction in dystonia with 1 ​h of DBS of the centrolateral thalamic nucleus, a first order node in the network downstream of the cerebellar nuclei. In contrast, 1 ​h of stimulation at a second order node in the short latency, disynaptic projection from the cerebellar nuclei, the striatum, did not show similar rapid modulation of dystonia. Our study introduces a robust paradigm for inducing acute, severe dystonia, and demonstrates that targeted modulation based on network principles powerfully rescues motor behavior. These data inspire the identification of a short latency therapeutic target for acquired dystonia and status dystonicus.

Childhood dementias, a group of neurological disorders are characterised by neurocognitive decline, with physical and psychosocial impacts for individuals. With therapy available for <5 ​% of childhood dementias, there is a high level of unmet need. Integration of biomarkers in clinical trials are important to characterize distinctive biological activities and interrogate targets for therapeutic development. This study reviewed four clinical trial registries to examine circulating biomarkers in childhood dementias. Findings from 262 studies were synthesized across 49/72 (68 ​%) childhood dementia disorders. Disease-related biomarkers were associated with 1) the primary pathophysiology 2) downstream pathogenic events 3) drug-related pharmacokinetics, safety and/or tolerability. The predominant biological measures were metabolites linked to the primary pathophysiological pathway (102 measures, 185 studies), while use of cytoskeletal proteins (3 measures, 15 studies), inflammatory mediators (19 measures, 24 studies), oxidative stress-related analytes (15 measures, 8 studies), neurotransmitters or related neuro-metabolites (3 measures, 5 studies) were limited. A range of potential biomarkers are used in clinical trials; however, their use is inconsistent and under utilised among conditions. Development of a panel of biomarkers has potential to interrogate and link shared biological pathways across the heterogeneity of childhood dementias to exert a significant impact for the development of disease-modifying therapies.

Astrocytes and oligodendrocytes, once considered passive support cells, are now recognized as active participants in the pathogenesis of Alzheimer's disease. Emerging evidence highlights the critical role that these glial cells play in the pathological features of Alzheimer's, including neuroinflammation, excitotoxicity, synaptic dysfunction, and myelin degeneration, which contribute to neurodegeneration and cognitive decline. Here, we review the current understanding of astrocyte and oligodendrocyte pathology in Alzheimer's disease and highlight research that supports the therapeutic potential of modulating astrocyte and oligodendrocyte functions to treat Alzheimer's disease.

Vascular endothelial growth factor (VEGF)-A is a main player in the development of neuropathic pain induced by chemotherapy and the pharmacological blockade of VEGF receptor (VEGFR) subtype 1 is a pain killer strategy. Interestingly, VEGF-A has been demonstrated to have also neuroprotective properties. The aim of the study was to investigate the neuroprotective role of VEGF-A against oxaliplatin neurotoxicity, attempting to discriminate pain-related and restorative signaling pathways. We used rat organotypic spinal cord slices treated with oxaliplatin, as an in vitro model to study chemotherapy-induced toxicity. In this model, 10 ​μM oxaliplatin caused a time-dependent release of VEGF-A, which was reduced by the astrocyte inhibitor fluorocitrate. Moreover, glia inhibition exacerbated oxaliplatin-induced cytotoxicity in a VEGF-A sensitive manner. Treatment with VEGF₁₆₅b, the main isoform of VEGF-A, prevented the oxaliplatin-induced neuronal damage (indicated by NeuN staining) and astrocyte activation (indicated by GFAP staining). In addition, the blockade of VEGFR-2 by the selective antibody DC101 blunted the protective action of VEGF₁₆₅b. In the same model, VEGF₁₆₅b increased the release of molecules relevant in pain signaling, like substance P and CGRP, as well as the mRNA expression of glutamate transporters (EAAT1 and EAAT2), similarly to oxaliplatin and these effects were prevented by the selective VEGFR-1 blocker antibody D16F7. In conclusion, VEGF-A plays a dichotomic role in an in vitro model of chemotherapy-induced toxicity, either promoting neuroprotection or triggering pain mediators release, depending on which of its two receptors is activated. The selective management of VEGF-A signaling is suggested as a therapeutic approach.

Amyloidoses, which are characterized by abnormal accumulation of amyloid proteins leading to organ dysfunction, represent a major therapeutic challenge. They include neurodegenerative diseases, such as Alzheimer disease (AD), tauopathies and synucleinopathies. Since amyloids are causative factors in these diseases, the importance of proteolytic methods to remove amyloid, such as immunotherapy and Proteolysis Targeting Chimera (PROTAC) technology, has been recognized. Immunotherapy removes target proteins by antibody-mediated reactions and is the most studied method in practical use for the treatment of AD. PROTAC is a small molecule that uses the ubiquitin-proteasome system to degrade intracellular target proteins and has demonstrated efficacy in clinical trials for other diseases. In addition, a new modality called photo-oxygenation has been developed. Photo-oxygenation is a method of selectively adding oxygen to amyloid using a photocatalyst, which is a small molecule compound that is activated by light. Studies both in vitro and in vivo have shown promising results in inhibiting amyloid aggregation and enhancing the clearance of amyloid proteins. In this review, we introduce and discuss these proteolytic modalities, and provide insights into potential future directions for the clinical application in amyloidoses.

More than 50 ​% of patients undergoing mechanical thrombectomy (MT) for ischemic stroke have a poor functional outcome despite timely and successful angiographic reperfusion, highlighting the need for adjunctive treatments to reperfusion therapy. Mitochondria are key regulators of cell fate, by controlling cell bioenergetics via oxidative phosphorylation (OXPHOS) and cell death through the mitochondrial permeability transition pore (mPTP). Whether these two main mitochondrial functions are altered by reperfusion and could represent a new cytoprotective approach remains to be elucidated in mice. Swiss male mice underwent either permanent or transient middle cerebral artery occlusion (pMCAO or tMCAO), with neuroscore evaluation and multimodal imaging. The area at risk of necrosis was evaluated by per-occlusion dynamic contrast-enhanced ultrasound. Final infarct size was assessed at day 1 by MRI. Cortical mitochondrial isolation was subsequently performed to assess mPTP sensitivity by calcium retention capacity (CRC) and OXPHOS. A cytoprotective treatment targeting mitochondria, ciclosporine A (CsA), was tested in tMCAO, to mimick the clinical situation of patients treated with MT. Reperfusion after 60 ​min of ischemia improves neuroscores but does not significantly reduce infarct size or mitochondrial dysfunction compared to permanent ischemia. CsA treatment at reperfusion mitigates stroke outcome, decreases final infarct size and improves mitochondrial CRC and OXPHOS. Mitochondrial dysfunctions, i.e. reduced mPTP sensitivity and decreased oxygen consumption rates, were observed in pMCAO and tMCAO regardless of the reperfusion status. CsA improved mitochondrial functions when injected at reperfusion. These suggest that both mPTP opening and OXPHOS alterations are thus early but reversible hallmarks of cerebral ischemia/reperfusion.