Frontiers in Molecular Neuroscience最新文献

Retinoic acid receptor β2 (RARβ2) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal regenerative effect. We have developed a first-in-class RARβ agonist drug, C286, that modulates neuron-glial pathways to induce functional recovery in a rodent model of sensory root avulsion. Here, using genome-wide and pathway enrichment analysis of avulsed rats' spinal cords, we show that C286 also influences the extracellular milieu (ECM). Protein expression studies showed that C286 upregulates tenascin-C, integrin-α9, and osteopontin in the injured cord. Similarly, C286 remodulates these ECM molecules, hampers inflammation and prevents tissue loss in a rodent model of spinal cord contusion C286. We further demonstrate C286's efficacy in human iPSC-derived neurons, with treatment resulting in a significant increase in neurite outgrowth. Additionally, we identify a putative efficacy biomarker, S100B, which plasma levels correlated with axonal regeneration in nerve-injured rats. We also found that other clinically available retinoids, that are not RARβ specific agonists, did not lead to functional recovery in avulsed rats, demonstrating the requirement for RARβ specific pathways in regeneration. In a Phase 1 trial, the single ascending dose (SAD) cohorts showed increases in expression of RARβ2 in white blood cells correlative to increased doses and at the highest dose administered, the pharmacokinetics were similar to the rat proof of concept (POC) studies. Collectively, our data suggests that C286 signalling in neurite/axonal outgrowth is conserved between species and across nerve injuries. This warrants further clinical testing of C286 to ascertain POC in a broad spectrum of neurodegenerative conditions.

Introduction: Treatment with the synaptic plasticity protein reelin has rapid antidepressant-like effects in adult corticosterone (CORT)-induced depressed rats, whether administered repeatedly or acutely. However, these effects remain unexplored in the context of post-partum depression (PPD).

Methods: This study investigated the antidepressant-like effect of a single injection of reelin in a CORT-induced model of PPD. Long-Evans female dams received either daily subcutaneous CORT (40 mg/kg) or saline injections (controls) from the post-partum day (PD) 2 to 22, and on PD22 were treated with a single intravenous reelin (3 μg) or vehicle injection.

Results: Reelin treatment fully normalized to control levels the CORT-induced increase in Forced Swim Test (FST) immobility and the decrease in reelin-positive cells in the subgranular zone of the intermediate hippocampus. It also increased the number of oxytocin-positive cells in the paraventricular nucleus (PVN), the number of reelin-positive cells in the dorsal and ventral hippocampus, and the dendritic complexity of newborn neurons in the intermediate hippocampus, causing a partial recovery compared to controls. None of these changes were associated with fluctuations in estrogen levels measured peripherally.

Discussion: This study brings new insights into the putative antidepressant-like effect of peripherally administered reelin in an animal model of PPD. Future studies should be conducted to investigate these effects on a dose-response paradigm and to further elucidate the mechanisms underlying the antidepressant-like effects of reelin.

Magnetic resonance spectroscopy (MRS) has been employed to investigate brain metabolite concentrations in vivo, and they vary during neuronal activation, across brain activity states, or upon disease with neurological impact. Whether resting brain metabolites correlate with functioning in behavioral tasks remains to be demonstrated in any of the widely used rodent models. This study tested the hypothesis that, in the absence of neurological disease or injury, the performance in a hippocampal-dependent memory task is correlated with the hippocampal levels of metabolites that are mainly synthesized in neurons, namely N-acetylaspartate (NAA), glutamate and GABA. Experimentally naïve rats were tested for hippocampal-dependent spatial memory performance by measuring spontaneous alternation in the Y-maze, followed by anatomical magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in the hippocampus and cortex. Memory performance correlated with hippocampal concentrations of NAA (p = 0.024) and glutamate (p = 0.014) but not GABA. Concentrations of glutamate in the cortex also correlated with spatial memory (p = 0.035). In addition, memory performance was also correlated with the relative volume of the hippocampus (p = 0.041). Altogether, this exploratory study suggests that levels of the neuronal maker NAA and the main excitatory neurotransmitter glutamate are associated with physiological functional capacity.

Introduction: Stroke, the second leading cause of death and disability in Europe, is primarily caused by interrupted blood supply, leading to ischemia-reperfusion (IR) injury and subsequent neuronal death. Current treatment options are limited, highlighting the need for novel therapies. Neural stem cells (NSCs) have shown promise in treating various neurological disorders, including stroke. However, the underlying mechanisms of NSC-mediated recovery remain unclear.

Methods: Eighty C57Bl/6-Tyrc-Brd mice underwent ischemic stroke induction and were divided into four groups: sham, stroke-affected, stroke-affected with basal cell medium injection, and stroke-affected with NSCs transplantation. NSCs, isolated from mouse embryos, were stereotaxically transplanted into the stroke-affected brains. Magnetic resonance imaging (MRI) and neurological scoring were used to assess recovery. Immunohistochemical analysis and gene expression assays were performed to evaluate pyroptosis and necroptosis markers.

Results: NSC transplantation significantly improved neurological recovery compared to control groups. In addition, although not statistically significant, NSCs reduced stroke volume. Immunohistochemical analysis revealed upregulation of Gasdermin D (GSDMD) expression post-stroke, predominantly in microglia and astrocytes. However, NSC transplantation led to a reduction in GSDMD signal intensity in astrocytes, suggesting an effect of NSCs on GSDMD activity. Furthermore, NSCs downregulated Mixed Lineage Kinase Domain-Like Protein (Mlkl) expression, indicating a reduction in necroptosis. Immunohistochemistry demonstrated decreased phosphorylated MLKL (pMLKL) signal intensity in neurons while stayed the same in astrocytes following NSC transplantation, along with increased distribution in microglia.

Discussion: NSC transplantation holds therapeutic potential in stroke recovery by targeting pyroptosis and necroptosis pathways. These findings shed light on the mechanisms underlying NSC-mediated neuroprotection and support their further exploration as a promising therapy for stroke patients.