Sodium Phenylbutyrate synthesis H R antagonism can prevent s

H3R antagonism can prevent seizure development and improve working memory through the activation of histaminergic neurons (Huang et al., 2004, Zhang et al., 2003). In addition, we have recently found that H3R antagonism protects against ischemia-reperfusion injury via histamine-independent mechanisms (Yan et al., 2014). Despite the above-mentioned findings supporting H3R blockade as generally neuroprotective via histamine-dependent or independent pathways, targeting of the H3R has not been viewed as a strategy for the treatment of TBI. It is thus imperative to explore the action of H3R antagonism and the role of the cell-type-specific postsynaptic histamine receptors in neurogenesis following TBI by selective Sodium Phenylbutyrate synthesis of H1R or H2R in NSCs or surrounding cells.
Results
Discussion With the exception of rehabilitation, there is currently no other effective and available therapy to improve neurological outcomes for patients in the late phase of TBI. Various preclinical and clinical trials have been undertaken for H3R antagonists in the treatment of neurodegenerative diseases and sleep disorders (Hu and Chen, 2017, Schwartz, 2011). In the present study, we found that H3R antagonism shows prominent neuroprotection against TBI during its late phase, with a remarkable reduction of neurological dysfunction and lesion size (Figure 1). Moreover, the enhanced neurogenesis after H3R antagonism contributes to this neuroprotection, since more neuroblasts are generated and differentiate into mature and functional neurons in the area of the penumbra (Figures 2A, 2B, and 5A–5J) (Piao et al., 2013). Our study thus indicated that the H3R may serve as a promising target for the clinical treatment of TBI through a robust elevation of neurogenesis. Given the limited endogenous neurogenesis after TBI (Figures 2A and 2B), H3R antagonists may be good potential candidate drugs for neurological recovery. Since both histamine-dependent and histamine-independent modes of action have been found to be related to the neuroprotection through H3R antagonism (Hu and Chen, 2012, Hu and Chen, 2017, Yan et al., 2014), we are interested in whether H3R antagonists promote neurogenesis in the context of TBI through activation of the histaminergic system. Our study demonstrates that the promotion of neurogenesis conferred by H3R antagonists is the result of activation of histaminergic neurons, since this improved neurological regeneration was completely halted when histamine was depleted by pharmacological treatments or by genetic blockage of histamine synthesis (Figures 2A and 2C). Although previous studies have implicated both the H1R and the H2R in the mechanism of action of histamine in neurogenesis (Molina-Hernandez and Velasco, 2008), the role of cell-type-specific postsynaptic histamine receptors in the present study is still unknown. We found that the H1R, but not the H2R, participates in the H3R antagonism-conferred neurogenesis and neuroprotection (Figures 2C–2F). To further investigate whether the NSC-specific H1R is involved in the action of neurological recovery, we generated Hrh1;Nestin and Hrh2;Nestin mice who have inducible and selective deletions of H1R or H2R in NSCs that otherwise do not affect embryonic and early postnatal development (Figure 3). Our results show that in NSCs, only the H1R, and not the H2R, is responsible for the promotion of neurogenesis and neuroprotection after TBI provided by H3R antagonism. In contrast, the glutamatergic excitatory projections are suggested to modulate neurogenesis during development and adulthood (Maithe Arruda-Carvalho et al., 2014, Zhao et al., 2008). However, we found, using Hrh1;CaMKIIα mice, that the H1R in CaMKIIα+ glutamatergic neurons is not involved in H3R antagonism-mediated neurogenesis (Figures S2B–S2D). This finding indicates that the regeneration of NSCs is largely mediated by a direct activation of endogenous H1R, rather than an indirect regulation of H1R in surrounding cells following H3R blockade. Taken together, our results suggest that, following TBI, H3R antagonism activates the histaminergic system and then H1R, but not H2R, in NSCs to boost neurogenesis and subsequent functional recovery.