Vitamin D3 treatment is associated with greater myelin integrity after intracerebral haemorrhage in mice

Abstract

Intracerebral haemorrhage (ICH) is a subtype of haemorrhagic stroke, which as a collective subtype of stroke, is associated with higher mortality and poorer functional outcomes. Management strategies targeting the long-term functional outcomes after ICH remain limited, as most current strategies are restricted to supportive therapy in the acute phase. In particular, myelin integrity is closely associated with functional outcomes in other disease models in the central nervous system, and as myelin is known to be disrupted in ICH, there is value in exploring treatment targets in protecting or regenerating myelin after ICH. Vitamin D3 (VitD), a readily available neurosteroid, has been shown to improve long term neurological recovery in demyelinating diseases such as multiple sclerosis, as well as acute central nervous system insults such as spinal cord injury by improving white matter integrity. However, although studies have demonstrated the efficacy of VitD in improving post-ischaemic stroke outcomes, the role of VitD in the management of haemorrhagic stroke remains inconclusive; this serves as another preclinical trial to evaluate the role of VitD supplementation in long term neurological recovery. This study also appears to be the first to explore the role of VitD in long term myelin integrity using a collagenase mouse model. In pursuit of the study objectives, a descriptive literature review on the response of myelin and oligodendrocyte-lineage cells in response to ICH and the mechanisms of action of VitD in stroke and various disease models is conducted. Experimental ICH was induced by a collagenase mouse model. Behavioural motor assessments were subsequently performed to compare the functional outcomes of treatment, experimental and sham arms, while histological analysis was performed on both the brain and cervical corticospinal tract (CST) to evaluate myelin integrity at different stages of injury. To explore potential downstream pathways, protein analysis by western blotting and preliminary in vitro studies were also performed. Behavioural motor assessments demonstrated a higher degree of functional recovery in the experimental arm, which correlated with higher myelin integrity observed in histological analysis of brain and cervical CST specimens. The pattern of appearance of peri-haematomal oligodendrocyte precursor cells (OPCs), which are precursors of myelin-producing cells, are also suggestive of higher myelin integrity in the experimental arm at the subacute phase of ICH. The pattern of vitamin D receptor (VDR) and retinoid X receptor gamma (RXR-g) upregulation, as demonstrated in protein analysis, suggested a role of the VDR-RXRg signalling in promoting myelin integrity after ICH. The preliminary results of in-vitro tests suggest a role of VDR-RXRg signalling in OPC differentiation, but such findings remain inconclusive. This study demonstrated the role of VitD supplementation in improving functional outcomes and myelin integrity in the subacute to chronic phase of ICH, as well as the potential pathways of action, namely the role of VDRRXRg signalling in promoting OPC differentiation. More preclinical trials should be performed to replicate such results, while clinical trials should also be conducted to evaluate the translational significance of such findings.