Envenomation by snakes is a major neglected human disease. Hospitalization and use of animal-derived antivenom are the primary therapeutic supports currently available. There is consensus that additional, not expensive, treatments that can be delivered even long after the snake bite are needed. We recently showed that the drug dubbed NUCC-390 shortens the time of recovery from the neuroparalysis caused by traumatic or toxic degeneration of peripheral motor neurons. These syndromes are characterized by the activation of a pro-regenerative molecular axis, consisting of the CXCR4 receptor expressed at the damaged site in neuronal axons and by the release of its ligand CXCL12α, produced by surrounding Schwann cells. This intercellular signaling axis promotes axonal growth and functional recovery from paralysis. NUCC-390 is an agonist of CXCR4 acting similarly to CXCL12α. Here, we have tested its efficacy in a murine model of neuroparalytic envenoming by a Papuan Taipan (Oxyuranus scutellatus) where a degeneration of the motor axon terminals caused by the presynaptic PLA2 toxin Taipoxin, contained in the venom, occurs. Using imaging of the neuromuscular junction and electrophysiological analysis, we found that NUCC-390 administration after injection of either the purified neuroparalytic Taipoxin or the whole Taipan venom, significantly accelerates the recovery from paralysis. These results indicate that NUCC-390, which is non-toxic in mice, should be considered for trials in humans to test its efficacy in accelerating the recovery from the peripheral neuroparalysis induced by Taipans. NUCC-390 should be tested as well in the envenomation by other snakes that cause neuroparalytic syndromes in humans. NUCC-390 could become an additional treatment, common to many snake envenomings, that can be delivered after the bite to reduce death by respiratory deficits and to shorten and improve functional recovery. We have taken here a different angle in the search for novel treatments of snake envenomings by focusing of the phase of recovery from the peripheral neuroparalysis caused by neurotoxic snakes. This is a critical period that may require mechanical ventilation and prolonged hospitalization. We have found a drug, dubbed NUCC-390, which accelerates the functional recovery from peripheral neuroparalysis caused by the Taipan venom in mice, by acting on the CXCR4 receptor. In fact, we found here that this receptor is expressed by the motor neuron at the site of damage that, in the case of many snake venoms containing presynaptic PLA2 neurotoxins, consists in the degeneration of the axon terminal. NUCC-390 binds to CXCR4 and acts similarly to its natural agonist the chemokine CXCL12α. The compound is not toxic and can be administered after the snakebite and therefore it has the potential of becoming a non-expensive addition to the currently available antisera treatment whose efficacy is limited by the need of delivery shortly after snakebite.

Snake envenoming is a major but neglected human disease in tropical and subtropical regions. Among venomous snakes in the Americas, coral snakes of the genus Micrurus are particularly dangerous because they cause a peripheral neuroparalysis that can persist for many days or, in severe cases, progress to death. Ventilatory support and the use of snake species-specific antivenoms may prevent death from respiratory paralysis in most cases. However, there is a general consensus that additional and non-expensive treatments that can be delivered even long after the snake bite are needed. Neurotoxic degeneration of peripheral motor neurons activates pro-regenerative intercellular signaling programs, the greatest of which consist of the chemokine CXCL12α, produced by perisynaptic Schwann cells, which act on the CXCR4 receptor expressed on damaged neuronal axons. We recently found that the CXCR4 agonist NUCC-390 promotes axonal growth. Here, we show that the venom of the highly neurotoxic snake Micrurus nigrocinctus causes a complete degeneration of motor axon terminals of the soleus muscle, followed by functional regeneration whose time course is greatly accelerated by NUCC-390. These results suggest that NUCC-390 is a potential candidate for treating human patients envenomed by Micrurus nigrocinctus as well as other neurotoxic Micrurus spp. in order to improve the recovery of normal neuromuscular physiology, thus reducing the mortality and hospital costs of envenoming.

We used α-Latrotoxin (α-LTx), the main neurotoxic component of the black widow spider venom, which causes degeneration of the neuromuscular junction (NMJ) followed by a rapid and complete regeneration, as a molecular tool to identify by RNA transcriptomics factors contributing to the structural and functional recovery of the NMJ. We found that Urocortin 2 (UCN2), a neuropeptide involved in the stress response, is rapidly expressed at the NMJ after acute damage and that inhibition of CRHR2, the specific receptor of UCN2, delays neuromuscular transmission rescue. Experiments in neuronal cultures show that CRHR2 localises at the axonal tips of growing spinal motor neurons and that its expression inversely correlates with synaptic maturation. Moreover, exogenous UCN2 enhances the growth of axonal sprouts in cultured neurons in a CRHR2-dependent manner, pointing to a role of the UCN2-CRHR2 axis in the regulation of axonal growth and synaptogenesis. Consistently, exogenous administration of UCN2 strongly accelerates the regrowth of motor axon terminals degenerated by α-LTx, thereby contributing to the functional recovery of neuromuscular transmission after damage. Taken together, our results posit a novel role for UCN2 and CRHR2 as a signalling axis involved in NMJ regeneration.

Peripheral nervous system (PNS) neurons, including motor neurons (MNs), possess a remarkable ability to regenerate and reinnervate target muscles following nerve injury. This process is orchestrated by a combination of intrinsic neuronal properties and extrinsic factors, with Schwann cells (SCs) playing a central role. Upon injury, SCs transition into a repair phenotype that allows axonal regeneration through molecular signaling and structural guidance. However, the identity of the SCs’ reprogramming factors is only partially known. We previously identified hydrogen peroxide (H₂O₂) as an early and key driver of nerve repair, inducing gene expression rewiring in SCs to support nerve re-growth. In this study, we quantitatively assessed the role of H₂O₂ in the activation of key pro-regenerative signaling pathways in SCs following sciatic nerve compression, specifically the extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun, which are essential for functional nerve recovery. Notably, we found that H₂O₂ neutralization does not impact degeneration, but it significantly affects the regenerative response. Collectively, our findings establish H₂O₂ as a promising regulator of the Schwann cell injury response at the injury site, linking oxidative signaling to the molecular mechanisms governing nerve regeneration.

Limb-Girdle Muscular Dystrophies (LGMDs) are genetically heterogeneous disorders primarily affecting proximal limb muscles. The most common form, LGMDR1, results from biallelic CAPN3 mutations encoding calpain-3, a muscle-specific protease. Recently, growing evidence implicates heterozygous CAPN3 variants in autosomal dominant disease (LGMDD4), with pathogenic mechanisms still incompletely understood. In a retrospective multicenter Italian study of patients harboring monoallelic CAPN3 variants (ClinicalTrials.gov NCT05956132), the p.Asp753Asn substitution was the most frequent change, detected in eight unrelated individuals. These patients, aged 6–80 years, exhibited a spectrum of presentations ranging from asymptomatic hyperCKemia and exertional myalgia to mild proximal weakness. Muscle biopsies showed mild, nonspecific myopathic changes, while calpain-3 expression was variably reduced. Structural modeling suggested that Asp753 may stabilize the Ca²⁺-bound conformation, with substitution potentially disrupting inter-domain interactions. Literature review identified 31 additional reports worldwide, confirming recurrence while highlighting marked phenotypic heterogeneity and limited clinical annotation. The aggregated evidence supports a pathogenic role for p.Asp753Asn, though the precise mechanism, potentially involving a dominant-negative effect, remains to be validated. These findings emphasize diagnostic challenges posed by single CAPN3 variants and underscore the need for integrated clinical, segregation, and functional studies to clarify pathogenic mechanisms, refine counseling, and guide patient-specific rehabilitation and therapeutic strategies.

Background/Objectives: This study evaluated a novel rehabilitation tool that combines prismatic adaptation (PA) and cognitive training through serious games (SGs) in patients with mild cognitive impairment (MCI) due to prodromal Alzheimer’s dementia or consequent to Parkinson’s disease. While non-pharmacological interventions have been shown to improve cognition or delay dementia onset, their underlying neurobiological mechanisms, such as brain plasticity, remain unclear. Leveraging studies suggesting neuromodulatory effects of PA, we investigated whether the combined PA+SGs treatment could influence plasticity-related mechanisms, assessed through brain-derived neurotrophic factor (BDNF) serum levels, compared to cognitive training with only SGs and standard cognitive rehabilitation (SCR). Methods: Twenty three MCI patients were randomized into three intervention groups: PA+SGs (experimental group), SG-only (control group), and SCR (control group), completing ten treatment sessions. Patients underwent neuropsychological assessments and blood sampling pre- and post-treatment. Results: At baseline, demographic, clinical, and biological characteristics were comparable across groups. Post-treatment, though differences from control groups were not statistically significant, the PA+SGs group showed significant within-group improvements in memory, with trend-level changes also in executive function and visuospatial abilities, which, however, did not reach the significance threshold. Notably, only the PA+SGs group exhibited increased BDNF levels, which positively correlated with memory and language performance. Conclusions: Our findings suggest that combining PA with cognitive training may enhance cognitive functioning in MCI patients, yielding results comparable to SCR. Furthermore, PA appears to enhance neuroplasticity mechanisms that may support the behavioral improvements observed in cognitive training. Future research should validate these findings and further explore the relationship between cognitive impairment and its rehabilitation, while also considering the underlying neurobiological mechanisms.