Migraine is a disabling neurovascular disorder with limited therapeutic options, especially for patients unresponsive to current treatments targeting calcitonin gene-related peptide (CGRP) signaling. The endocannabinoid system (ECS) has emerged as a promising alternative for migraine modulation, offering analgesic, anti-inflammatory, and neuroimmune-regulatory effects through its main ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their degrading enzymes. This review provides an updated map of endocannabinoid components in central and peripheral migraine-relevant regions, highlighting their spatial distribution and functional regulation in animal models. We summarize the available preclinical evidence supporting the anti-nociceptive effects of endocannabinoid-degrading enzyme inhibitors and cannabinoid receptor agonists/antagonists, with particular emphasis on the therapeutic potential of multi-target compounds. Moreover, we explore non-canonical ECS pathways, including TRPV1, D2 dopamine receptors, serotonergic and ion channel interactions, and their roles in modulating CGRP release and trigeminovascular signaling to treat migraine pathophysiology. Finally, we propose two sleep-related directions for treatments involving ECS modulation of circadian rhythms and glymphatic clearance. Although human translational data are limited, the ECS offers a multifaceted framework for developing next-generation therapeutics targeting migraine pathophysiology.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration and muscle weakness, generally leading to death due to respiratory failure within 2–5 years of symptom onset. Current Food and Drug Administration-approved drugs —riluzole, edaravone, and tofersen — offer limited clinical benefit due to ALS multifactorial etiology and high heterogeneity. To bypass this therapeutic letdown, we previously exploited network medicine and drug repurposing strategies. Leveraging the SAveRUNNER algorithm, we identified several potentially repurposable candidates, including clomipramine (Anafranil®), mianserin (Lantanon®/Tolvon®), and modafinil (Provigil®). Here, we evaluated the in vivo efficacy of these compounds in Drosophila models of ALS, precisely those expressing pan-neuronal human SOD1A4V or SOD1G85R mutations. Our results demonstrate that clomipramine is the most promising candidate, ameliorating lifespan reduction, improving climbing abilities, and mitigating both genomic instability and inflammation, key pathological hallmarks of these SOD1-ALS models. Despite needing further validation in higher organisms, our Drosophila findings represent preliminary yet significant support for clomipramine's action as an add-on treatment for SOD1-ALS.

Substance use disorders (SUDs) are chronic disorders marked by intense and compulsive drug-seeking behavior, coupled with a high risk of relapse. Different theories have emerged over time regarding mechanisms that induce and exacerbate SUDs. This review explores new and evolving evidence on the role of reward systems and processes and aligns those conceptual frameworks with neuroplastic and neuroinflammatory mechanisms and potential therapeutic targets. As the addiction cycle progresses, substance use shifts to long-term chronic use, marked by reduced hedonic effects and intensified compulsion. Thus, a “euphoria reward” model fails to completely capture the progression and complexity of SUDs. Substantive research suggests that the brain circuits that subserve pleasure and craving are distinct, which may explain why individuals with SUDs continue to seek out substances in the absence of pleasure. Additionally, the alleviation of negative affect, anhedonia, post-acute withdrawal symptoms, or other symptoms, may play a key part in preventing relapse. Recent studies emphasize the critical roles of neuroinflammation and oxidative stress in shaping SUDs by altering neural circuitry involved in reward, motivation, negative affect, and decision-making, thereby heightening relapse risk. Molecular adaptations, neuroplasticity and neuroinflammation appear to be important mediators of these changes. This review examines toxicity across the brain, heart and liver, focusing on mechanisms of neuroinflammation, neuroplasticity and gasotransmitter systems. It is proposed that an emphasis on developing pharmacotherapies targeting these mechanisms, while also addressing interactions between the brain and peripheral systems, both as consequences of SUDs and as drivers of the progression of SUDs, may provide new success in SUD therapeutic development.

Vagus nerve stimulation (VNS) represents a neuromodulation technique that has shown potential in the treatment of various diseases. However, conventional VNS therapy is constrained by the requirement for implanted electrodes, primarily due to the scarcity of appropriate vagal cutaneous branches. Here, a neural bridging method was employed to connect the sensory nerve with the vagus nerve, thereby facilitating transcutaneous modulation of autonomic nerve function and addressing depressive disorders. Results showed that end-to-side neurorrhaphy induced robust axonal regeneration while preserving vagus nerve integrity. Neural tracing confirmed cervical nerve-to-nucleus tractus solitarius projections. Postoperative auricular stimulation significantly evoked 3.46-fold higher c-Fos+ neurons in the nucleus tractus solitarius versus sham controls. In depressed mice, this approach normalized behavioral deficits. Further investigations revealed concomitant improvements in non-rapid eye movement sleep architecture and suppression of hippocampal neuroinflammatory pathways (e.g., TNF, RNA-seq p ​< ​0.001). Together, this study developed a neural-bridging approach in mice that surgically connected a cutaneous sensory nerve to the cervical vagus nerve. Subsequent gentle auricular stimulation robustly activated the brainstem vagal nucleus and improved depression-like behaviors and sleep, alongside reduced hippocampal inflammatory signaling. As a preclinical proof-of-concept study, translational feasibility and long-term safety in humans require rigorous evaluation.

Cyanide exerts its toxic effects primarily by inhibiting mitochondrial Complex IV (Cytochrome c oxidase, CCOx). Recent studies have shown that mammalian cells can endogenously produce cyanide from glycine via a lysosomal pathway. At low concentrations, cyanide may play regulatory roles, but at higher levels, it causes metabolic inhibition. Here we show that Down syndrome (DS) cells and tissues exhibit significant overproduction of cyanide, contributing to cellular metabolic suppression. DS rats show elevated blood cyanide levels, and their tissues generate more cyanide than wild-type controls—both under basal conditions and following glycine supplementation. Similarly, human DS fibroblasts produce higher levels of cyanide than healthy control cells. We attribute this increased cyanide production in DS to the marked downregulation of thiosulfate sulfurtransferase (TST, also known as rhodanese), the key enzyme responsible for cyanide detoxification. Importantly, suppression of lysosomal cyanide production in DS cells (through cyanide scavengers, lysosomal deacidification, or inhibition of serine/glycine conversion) improves cellular bioenergetics and/or enhances cell proliferation rates. Previous work has implicated excessive hydrogen sulfide (H2S) production, another endogenous gaseous signaling molecule that inhibits CCOx, in DS-associated metabolic suppression. Our current findings indicate that cyanide overproduction may also contribute to this dysfunction. Cyanide and H2S may act cooperatively on the same molecular target. These results open the possibility of developing therapeutic strategies that target cyanide or both cyanide and H2S to counteract DS-associated metabolic impairment.

This study investigates distinct neuroinflammatory patterns in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) using multi-tracer PET and MR imaging. Eight NMOSD (5F/3M; median age 36.5) and six MOGAD patients (2F/4M; median age 34.0) underwent PET scans with [18F]FDG (glucose metabolism), the translocator protein (TSPO) ligand [18F]PBR06 (glial activation), and [11C]acetate (astrocyte metabolism), integrated with synchronous 3T MRI sequences. Standardized uptake value ratios (SUVRs) referenced to contralateral white matter (WM) or whole brain were statistically compared across specific anatomic regions: active lesions, normal-appearing WM (NAWM), and periventricular zones. Both groups exhibited elevated [18F]PBR06 SUVR within lesions compared to contralateral WM, marking microgliosis. Crucially, NMOSD lesions showed significantly lower [18F]FDG SUVR (p ​= ​0.01; metabolic impairment) and [11C]acetate SUVR (astrocyte dysfunction) than MOGAD lesions. Lesional [18F]PBR06 uptake correlated significantly with [18F]FDG uptake. Beyond lesions, NMOSD patients had higher [18F]FDG SUVR in cerebellar WM (p ​< ​0.01) and periventricular regions near the fourth ventricle (p ​= ​0.01), and higher [18F]PBR06 SUVR in cerebral WM (p ​= ​0.03), contrasted with MOGAD. With lesions in both disorders demonstrating microgliosis, NMOSD exhibited more severe lesion-specific metabolic suppression and astrocyte dysfunction, reflected in reduced [11C]acetate uptake, coupled with regional inflammation (microgliosis) and hypermetabolism. These differential multi-tracer PET patterns, especially the combined reduction in lesional astrocytic ([11C]acetate) and metabolic ([18F]FDG) markers in NMOSD versus MOGAD, highlight multimodal PET/MRI as a powerful tool for differentiating NMOSD and MOGAD pathophysiology.