Clinical, Neurophysiological and Histopatological correlations in Pure Neural Leprosy

Although neuropathy remains one of the most problematic issues faced by leprosy patients, the evolving process of its findings continues a challenge particularly in pure neural leprosy (PNL). We evaluated neurological examination, nerve conduction studies and histhopathological data of patients with PNL and ulnar neuropathy. Patients with longer duration of symptoms had reduction in the motor conduction velocities and patients with fibrosis in the biopsy had axonal damage in the nerve conduction studies. This suggests that focal demyelination may be present in leprosy patients at the moment of the diagnosis and be related to the duration of the neuropathy.

CD38 dependent NAD+ depletion contributes to oligodendrocyte loss and inhibition of myelin regeneration

Western-style diets cause disruptions in myelinating cells and astrocytes within the CNS. We identified increased CD38 expression in the mouse spinal cord following chronic high fat consumption or focal demyelinating injury. CD38-catalytically inactive mice are significantly protected from high fat-induced NAD+ depletion, oligodendrocyte loss, oxidative damage, and astrogliosis. 78c, a CD38 inhibitor, increased NAD+ and attenuated neuroinflammatory changes in astrocytes induced by saturated fat. Conditioned media from saturated fat-treated astrocytes impaired oligodendrocyte differentiation pointing to indirect mechanisms of oligodendrogliopathy. Combined saturated fat and lysolecithin demyelination in cerebellar slices resulted in additional deficits in myelin proteins that were mitigated by concomitant 78c treatment. Importantly, oral 78c increased counts of oligodendrocytes and remyelinated axons after focal demyelination. Our findings suggest that high fat diet impairs oligodendrocyte survival and differentiation through astrocyte-linked mechanisms mediated by the NAD+ase CD38, and highlight the use of CD38 inhibitors as potential therapeutic candidates to improve myelin regeneration.

Dynamic response of microglia/macrophage polarization following demyelination in mice

Background The glial response in multiple sclerosis (MS), especially for recruitment and differentiation of oligodendrocyte progenitor cells (OPCs), predicts the success of remyelination of MS plaques and return of function. As a central player in neuroinflammation, activation and polarization of microglia/macrophages (M/M) that modulate the inflammatory niche and cytokine components in demyelination lesions may impact the OPC response and progression of demyelination and remyelination. However, the dynamic behaviors of M/M and OPCs during demyelination and spontaneous remyelination are poorly understood, and the complex role of neuroinflammation in the demyelination-remyelination process is not well known. In this study, we utilized two focal demyelination models with different dynamic patterns of M/M to investigate the correlation between M/M polarization and the demyelination-remyelination process. Methods The temporal and spatial features of M/M activation/polarization and OPC response in two focal demyelination models induced by lysolecithin (LPC) and lipopolysaccharide (LPS) were examined in mice. Detailed discrimination of morphology, sensorimotor function, diffusion tensor imaging (DTI), inflammation-relevant cytokines, and glial responses between these two models were analyzed at different phases. Results The results show that LPC and LPS induced distinctive temporal and spatial lesion patterns. LPS produced diffuse demyelination lesions, with a delayed peak of demyelination and functional decline compared to LPC. Oligodendrocytes, astrocytes, and M/M were scattered throughout the LPS-induced demyelination lesions but were distributed in a layer-like pattern throughout the LPC-induced lesion. The specific M/M polarization was tightly correlated to the lesion pattern associated with balance beam function. Conclusions This study elaborated on the spatial and temporal features of neuroinflammation mediators and glial response during the demyelination-remyelination processes in two focal demyelination models. Specific M/M polarization is highly correlated to the demyelination-remyelination process probably via modulations of the inflammatory niche, cytokine components, and OPC response. These findings not only provide a basis for understanding the complex and dynamic glial phenotypes and behaviors but also reveal potential targets to promote/inhibit certain M/M phenotypes at the appropriate time for efficient remyelination.