Histamine H1 Receptors in Neural Stem Cells Are Required for the Promotion of Neurogenesis Conferred by H3 Receptor Antagonism following Traumatic Brain Injury

Abstract

Summary The neurological recovery following traumatic brain injury (TBI) is limited, largely due to a deficiency in neurogenesis. The present study explores the effects of histamine H3 receptor (H3R) antagonism on TBI and mechanisms related to neurogenesis. H3R antagonism or H3R gene knockout alleviated neurological injury in the late phase of TBI, and also promoted neuroblast differentiation to enhance neurogenesis through activation of the histaminergic system. Histamine H1 receptor, but not H2 receptor, in neural stem cells is shown to be essential for this promotion by using Hrh1 fl/fl ;Nestin CreERT2 and Hrh2 fl/fl ;Nestin CreERT2 mice. Moreover, increase in mature and functional neurons at the penumbra area conferred by H3R antagonism was abrogated in Hrh1 fl/fl ;Nestin CreERT2 mice. Taken together, H3R antagonism provides neuroprotection against TBI in the late phase through the promotion of neurogenesis, and the H1 receptor in neural stem cells is required for this action. H3R may serve as a new target for clinical treatment of TBI.

Histamine H3 Receptor Antagonist Enhances Neurogenesis and Improves Chronic Cerebral Hypoperfusion-Induced Cognitive Impairments

“…The previous study suggested that H3R antagonist improves neurogenesis in TBI-induced injury through activating the histaminergic system (Liao et al, 2019). Our findings suggested that thioperamide promoted proliferation of NE-4C stem cells through activating CREB signaling and subsequently promoted the BDNF production.…”

“…Strategies that increase adult neurogenesis have been researched for their therapeutic potential to treat CNS disorders (Zhu et al, 2004;Yau et al, 2014;Hollands et al, 2016;Morello et al, 2018). Inhibition of H3R can protect against traumatic brain injury (TBI)-induced injury by improving neurogenesis (Liao et al, 2019). H3R antagonist increased the adult hippocampal neurogenesis in aged mice (Guilloux et al, 2017).…”

“…Here, we suggest that thioperamide, a H3R antagonist, promotes proliferation of NE-4C stem cells and enhances neurogenesis in DG and SVZ region in CCH-induced injury. Thioperamide is the most widely used experimental selective H3R antagonist which can promote the production of histamine (Liao et al, 2019). Although thioperamide has high affinity for H4R, it is not expressed abundantly in the CNS.…”

“…Inhibition of H3R can protect against ischemic injury by enhancing autophagy (Yan et al, 2014). The H3R antagonist protects against traumatic brain injury (TBI) by regulating H1R (Liao et al, 2019), and also ameliorates the cognitive deficits induced by N-methyl-Daspartic acid receptor (NMDAR) antagonists like ketamine and MK-801 (Eissa et al, 2018). Inhibiting H3R also improves context discrimination task in aged mice (Guilloux et al, 2017).…”

Neurogenic Niche Conversion Strategy Induces Migration and Functional Neuronal Differentiation of Neural Precursor Cells Following Brain Injury

“…B rain injury is often accompanied by neuron loss and scar formation [1][2][3]. Neural precursor/stem cells (NP/ SCs), administered by either direct intracerebral injection or systemic injection after brain injury, have been used to reduce neuron loss and improve neurological functional recovery [4][5][6]. However, the effects of exogenous NP/SCs hinder the restoration of brain function, primarily due to the low survival rate of grafted cells in host tissues [7,8], which may be caused by mechanical damage, acute inflammation, immunological rejection, or a lack of trophic signals [9].…”