Protection Of Histamine H3 Receptor Antagonists Against Traumatic Brain Injury And The Involved Mechanisms

The neurological recovery following traumatic brain injury (TBI) is limited, probably due to the deficiency of neurogenesis. Histamine H3 receptor (H3R) negatively regulates the synthesis and release of neuronal histamine, which is suggested to be implicated in brain development and neurogenesis. Therefore, it is intriguing to explore the effects of H3R antagonists on TBI and the neurogenesis related mechanism. The H3R blockade reduced lesion volume and alleviated the motor dysfunction in beam-balance walk test and hanging wire test at the late phase after TBI, which can be reversed by H3R agonist. Moreover, the H3R knockout showed a protection in terms of the lesion volume and the motor function, but no further augment of this protection was observed after H3R antagonism in these H3R-/- mice. The H3R antagonists also increased the number of neuroblasts in the subventricular zone and subgranular zone after TBI. This action was reversed after the application of α-FMH, an inhibitor of histidine decarboxylase to block histamine synthesis or in histidine decarboxylase knockout mice. Furthermore, H1 receptor antagonist but not H2 antagonist reversed the action of H3 receptor antagonists. By using Hrhlf1/f1;NestinCreERT2 and Hrh2f1/f1;NestinCreERT2 mice, it is found that the H1 receptor, but not H2 receptor, in neural stem cells was involved in the increase of neuroblast number conferred by H3 receptor antagonist. It suggests that H3R antagonists activate histaminergic neurons and subsequent H1 receptor in neural stem cells to promote neurogenesis. Additionally, we found that H3R antagonists had no effect on the proliferation but promoted the differentiation of neural stem cells into neuroblasts to increase their number. Those new generated neuroblasts can migrate and differentiate into mature neurons at the penumbra area to contribute to functional recovery following H3R antagonism.Our study demonstrates that H3R antagonists display neuroprotection against TBI through promoting neurogenesis; the activation of histaminergic neuron and H1 receptor in neural stem cells are required for this protection. Therefore, H3R may serve as a new target for the clinical treatment of TBI, and H3R antagonists can be the potential candidate drugs for the therapy.