Mehrnaz Jafarian-Tehrani

In the central nervous system, oligodendrocytes extend their processes to wrap axons to form myelin sheaths, ensuring saltatory conduction of action potentials and providing trophic support for the axon. Our previous work demonstrated that pharmacological activation of α-secretase promotes myelin protection and remyelination after both ex vivo and in vivo demyelination. Based on these findings, the present study aims to investigate the role of oligodendroglial ADAM10 (OLA10; a member of the a-secretase family) in myelin development and maintenance. Using an inducible knockout mouse model for OLA10 (KOOL-A10), we demonstrated that OLA10 deficiency results in delayed maturation of OPC in primary culture, and altered myelination in primary neuron/glia co-culture. Furthermore, an induction of OLA10 deficiency in adult mice was associated with an alteration of myelin sheath thickness and long-term motor and cognitive deficit in males but not in females. Overall, our study highlights the subtle but significant role of ADAM10 expressed by oligodendrocytes in the formation and maintenance of the myelin over time, while emphasizing a sexual dimorphism that carries important relevance for current research.

Increasing findings suggest that demyelination may play an important role in the pathophysiology of brain injury, but the exact mechanisms underlying such damage are not well known. Mechanical tensile strain of brain tissue occurs during traumatic brain injury. Several studies have investigated the cellular and molecular events following a static tensile strain of physiological magnitude on individual cells such as oligodendrocytes. However, the pathobiological impact of high-magnitude mechanical strain on oligodendrocytes and myelinated fibers remains under investigated. In this study, we reported that an applied mechanical tensile strain of 30% on mouse organotypic culture of cerebellar slices induced axonal injury and elongation of paranodal junctions, two hallmarks of brain trauma. It was also able to activate MAPK-ERK1/2 signaling, a stretch-induced responsive pathway. The same tensile strain applied to mouse oligodendrocytes in primary culture induced a profound damage to cell morphology, partial cell loss, and a decrease of myelin protein expression. The lower tensile strain of 20% also caused cell loss and the remaining oligodendrocytes appeared retracted with decreased myelin protein expression. Finally, high-magnitude tensile strain applied to 158N oligodendroglial cells altered myelin protein expression, dampened MAPK-ERK1/2 and MAPK-p38 signaling, and enhanced the production of reactive oxygen species. The latter was accompanied by increased protein oxidation and an alteration of anti-oxidant defense that was strain magnitude-dependent. In conclusion, mechanical stretch of high magnitude provokes axonal injury with significant alterations in oligodendrocyte biology that could initiate demyelination.

Traumatic brain injury (TBI) and its consequences represent one of the leading causes of death in young adults. This lesion mediates glial activation and the release of harmful molecules and causes brain edema, axonal injury, and functional impairment. Since glial activation plays a key role in the development of this damage, it seems that controlling it could be beneficial and could lead to neuroprotective effects. Recent studies show that minocycline suppresses microglial activation, reduces the lesion volume, and decreases TBI-induced locomotor hyperactivity up to 3 months. The endocannabinoid system (ECS) plays an important role in reparative mechanisms and inflammation under pathological situations by controlling some mechanisms that are shared with minocycline pathways. We hypothesized that the ECS could be involved in the neuroprotective effects of minocycline. To address this hypothesis, we used a murine TBI model in combination with selective CB1 and CB2 receptor antagonists (AM251 and AM630, respectively). The results provided the first evidence for the involvement of ECS in the neuroprotective action of minocycline on brain edema, neurological impairment, diffuse axonal injury, and microglial activation, since all these effects were prevented by the CB1 and CB2 receptor antagonists.

Wnt signaling is required for neurogenesis, the fate of neural progenitors, the formation of neuronal circuits during development, neuron positioning and polarization, axon and dendrite development and finally for synaptogenesis. This signaling pathway is also implicated in the generation and differentiation of glial cells. In this review, we describe the mechanisms of action of Wnt signaling pathways and their implication in the development and correct functioning of the nervous system. We also illustrate how a dysregulated Wnt pathway could lead to psychiatric, neurodegenerative and demyelinating pathologies. Lithium, used for the treatment of bipolar disease, inhibits GSK3β, a central enzyme of the Wnt/β-catenin pathway. Thus, lithium could, to some extent, mimic Wnt pathway. We highlight the possible dialogue between lithium therapy and modulation of Wnt pathway in the treatment of the diseases of the nervous system.

Permanent olfactory dysfunction can often arise after traumatic brain injury (TBI) and while one of the main causes is the immediate loss of neurons in the olfactory bulb (OB), the emergent neuroinflammatory environment following TBI may further promote OB deterioration. Therefore, we examined the effects of acute anti-inflammatory treatment with minocycline on post-TBI olfactory behavior and on OB surface. The mouse model of closed-head injury by mechanical percussion was applied to anesthetized Swiss mice. The treatment protocol included three injections of minocycline (i.p.) at 5 min (90 mg/kg), 3 h, and 9 h (45 mg/kg) post-TBI. An olfactory avoidance test was run up to 12 weeks post-TBI. The mice were then sacrificed and their OB surface was measured. Our results demonstrated a post-TBI olfactory behavior deficit that was significant up to at least 12 weeks post-TBI. Additionally, substantial post-TBI OB atrophy was observed that was strongly correlated with the behavioral impairment. Minocycline was able to attenuate both the olfactory lesions and corresponding functional deficit in the short and long term. These results emphasize the potential role of minocycline as a promising neuroprotective agent for the treatment of TBI-related olfactory bulb lesions and deficits.