Stroke and multiple sclerosis involve oxygen and nutrient deprivation in the brain as well as inflammation, all of which lead to the release of glutamate and ATP. These compounds can cause excitotoxicity, contributing to neuronal and glial damage. Purinergic signaling, mediated by ATP and adenosine, regulates neuroinflammatory and neuroprotective mechanisms, playing a pivotal role in CNS injury. Key elements such as pannexin-1 hemichannels, calcium homeostasis modulator-1 (CalHM1), purinergic P2X7 receptors, and downstream intermediaries of ATP release contribute to neurotoxicity and inflammatory processes. Notably, P2X7 and P2X4 receptors are critical targets for reducing neuronal damage caused by microglia-mediated inflammation and repair, respectively. Additionally, the interaction between purinergic signaling and GABA type A (GABA_A) receptors opens new therapeutic possibilities by potentially promoting a balance in neurotransmission modulation and mitigating excitotoxicity. Experimental evidence and recent pharmacological developments, including P2X7 antagonists, P2X4 positive allosteric modulators, P1 agonists, and modulators of GABA_A receptors, offer promising avenues for translating preclinical findings into effective therapies for cerebrovascular diseases. Further clinical investigations are necessary to validate these interventions to attenuate tissue damage and foster repair in multiple sclerosis lesions and post-ischemic penumbra.

A large wave of myelination in the central nervous system (CNS) of mammals occurs during postnatal development, coinciding with the lactation period. High prolactin (PRL) levels are present in maternal milk; however, the role of milk PRL in lactating offspring remains under‐investigated. This study explores whether PRL influences myelination during postnatal development in lactating and prepubertal mice. PRL and its receptors (PRLRs) are found in white matter (WM) tracts of lactating mice, but PRL mRNA is not expressed locally, supporting that the hormone derives from maternal milk, since the pituitary gland from neonatal mice does not secrete PRL. The absence of PRLRs (in PRLR knockout [KO] mice) results in a hypomyelinated phenotype characterized by a reduced corpus callosum volume, decreased myelin staining in WM tracts ( cingulum, corpus callosum and dorsal fornix ), lower myelin basic protein (MBP) expression levels, and a reduced number of oligodendroglial cells, as revealed by fewer OLIG2‐positive cells in PRLR‐KO nursing pups at postnatal day (PD) 12. The hypomyelination observed in PRLR‐KO nursing pups continues into the prepubertal stage (PD28), when locomotor alterations (reduced distance traveled and decreased velocity of movements) manifest in PRLR‐KO mice. These findings show that the lack of PRL signaling leads to brain hypomyelination in neonatal mice and negatively affects locomotor function at the prepubertal stage, thereby supporting the notion that PRL is required for adequate myelination during postnatal development.

Amphibians are an important vertebrate model system to understand anatomy, genetics and physiology. Importantly, the brain and spinal cord of adult urodels (salamanders) have an incredible regeneration capacity, contrary to anurans (frogs) and the rest of adult vertebrates. Among these amphibians, the axolotl ( Ambystoma mexicanum ) has gained most attention because of the surge in the understanding of CNS regeneration and the recent sequencing of its whole genome. However, a complete comprehension of the brain anatomy is not available. In the present study we created a magnetic resonance imaging atlas of the in vivo neuroanatomy of the juvenile axolotl brain. This is the first MRI atlas for this species and includes 3 levels: 1) 80 regions of interest (ROIs); 2) a division of the brain according to the embryological origin of the neural tube, and 3) left and right hemispheres. Additionally, we localized the myelin rich regions of the juvenile brain. The atlas, the template that the atlas was derived from, and a masking file, can be found on Zenodo at DOI: 10.5281/zenodo.4311937. This MRI brain atlas aims to be an important tool for future research of the axolotl brain and that of other amphibians.

Fused deposition modeling (FDM) is an emerging trend for producing nerve guidance conduits (NGCs). This technique allows distinct designs and dimensions to mimic peripheral nerve architecture and promote nerve regeneration. In this study, commercially available TPU 90A and 95A filaments were used for the fabrication of hollow simple wall (non-porous), grooved and gyroid multichannel conduits. The segmented polyurethanes were identified as PBA-MDI-BO-based polyurethanes by ¹H NMR, FTIR and Raman spectroscopy. Thermal analyses, such as DSC and TGA, demonstrated that both TPUs possess sufficient thermal stability to be processed safely under the printing conditions employed. Tensile mechanical tests accounted for their differences in hard segment content in agreement with the Shore A hardness. The measured elastic modulus, in particular, was within a range that may be advantageous for peripheral nerve repair. The gyroid multichannel design showed enhanced resistance to radial compression and highly interconnected internal structure that supported primary neural cell viability and preserved cellular functionality. Therefore, polyurethane-based nerve guidance conduits can be manufactured by FDM, rendering high printability, favorable mechanical performance without compromising biocompatibility.

Oligodendrocyte precursor cells express GABA _A Rs and release GABA into the extracellular milieu; however, direct consequences of receptor activation remain unclear. In this work, we demonstrate that positive allosteric modulation of the GABA _A R increases cell survival in vitro and promotes morphological changes associated with maturation. Both effects are generated by an increase in intracellular Ca ²⁺ and activation of Ca ²⁺ -CaM-dependent kinases signaling pathway, which subsequently promote AKT phosphorylation, triggering antiapoptotic signals.

Myelination of axons by oligodendrocytes (OLs) greatly improves information processing in the brain; consequently, compromised myelin negatively impacts brain function. Young-adult Costello Syndrome (CS) patients present with learning disabilities and regression of psychomotor skills in correlation with abnormal brain white matter, delayed myelination, and dysmyelination. This suggests the involvement of OLs and myelin in abnormal brain physiology during and beyond development; however, the neuropathophysiology of CS remains poorly understood. Replacing the endogenous HRas gene with the CS-causing HRasG12V mutant gene in adult OLs (pHRasG/+ mice) induces ultrastructural myelin abnormalities; nonetheless, any functional impact is unknown. Here we show robust learning - but not memory - deficits in pHRasG/+ males and modest, delayed learning issues in females. Learning phenotypes are transient, likely involving compensatory responses from the OL lineage and microglia. Diffusion-weighted magnetic resonance imaging reveals region- and sex-dependent compromised myelin microstructure, coinciding with the peak of learning issues. Remarkably, pharmacological control of nitric oxide synthase 2 restores learning in male pHRasG/+ mice. Our study supports the notion that abnormal nitric oxide signaling in mature OLs affects learning, suggests a chronic impact of myelin-driven mechanisms in CS neuropathology, and proposes molecular targets with therapeutic potential for CS.