Vitamin D promotes sensorimotor function recovery by suppressing TNF receptor-1 initiated neuronal death after experimental intracerebral hemorrhage

Abstract

Intracerebral Hemorrhage (ICH) is a catastrophic neurological event that not only threatens patients’ lives but often results in motor and sensory deficits in surviving patients. The incidence of ICH is 30% of cases per 100,000 people per year. This percentage is expected to be increased in the coming decades because of the aging population and shifting diet habits in high fat and cholesterol. Current treatments for ICH are unsatisfactory and the prognosis remains poor. Treatments of ICH are very limited to symptomatic relief and rehabilitation. With an increasing understanding of ICH physiopathology, more studies reported for new therapies. Unfortunately, most of the results remain inconclusive. Hereby, we aim to find an alternative to treating ICH.

Vitamin D3 (Vit-D) is known as a secosteroid and is predominantly associated with peripheral calcium homeostasis. Increasing studies revealed that Vit-D has broader physiological roles in immune cell modulation, cell-cycle control, and maintaining neurological and muscular functions. Delivery of Vit-D to stroke patients showed benefits in the recovery of neurofunctions. Laboratory studies demonstrated that Vit-D promoted neuron survival and improved neurofunction recovery by promoting neurotrophic factors release, modulating oxidative hyperactivity, and reducing neuroinflammatory cytokines production. However, very little amounts of research investigated the use of Vit-D in hemorrhagic stroke. Therefore, it drove us to study the effects of Vit-D in the treatment of ICH.

In the present study, a standardized collagenase-induced rodent ICH model with moderate injury was enrolled to study the therapeutic potential of Vit-D. Two doses of cholecalciferol, Vit-D 1000IU/kg, and Vit-D 2000IU/kg, were given to the post-ICH mice daily for 28 days. Three neurofunctional assessments were used to evaluate the sensorimotor function recovery. Post-ICH mice benefited from all Vit-D treatments by promoting neurofunctional recovery. No significant difference was found between the two doses of Vit-D except faster functional recovery was observed with the higher dose. Besides, more neurons in perihematomal areas were preserved with Vit-D treatments and the cellular apoptosis was attenuated by mediating the TNF receptor-1 expression. The results were parallel to the sensorimotor performance.

Furthermore, embryonic cerebral cortical neurons were cultured in a primary culture system to investigate the direct effects of Vit-D in regulating neuronal apoptosis. Recombinant TNF-alpha was applied to the culturing neurons to initiate the extrinsic apoptosis pathway. Vit-D or TNF-alpha antagonist were also given to the neurons for 48 hours to compromise the activation of this pathway. The in vitro data presented similar results to those found in vivo. Vit-D effectively reduced neuronal apoptosis by attenuating the expression level of TNF receptor-1 as the TNF-alpha antagonist did.

Finally, the impact of the current study was first to demonstrate Vit-D could be an effective anti-inflammatory agent to mediate TNF receptor-1 initiated neuronal death after ICH. Sensorimotor functions were restored after Vit-D treatments and Vit-D 2000IU/kg might be an optimum dose to treat ICH with moderate injury. Further studies of other proinflammatory responses with Vit-D treatment after ICH are encouraged.