Abstract
Evidence points to a dual role of histamine in microglia-mediated neuroinflammation, a key pathological feature of several neurodegenerative pathologies. Moreover, histamine has been suggested as a modulator of adult neurogenesis. Herein, we evaluated the effect of histamine in hippocampal neuroinflammation and neurogenesis under physiological and inflammatory contexts. For that purpose, mice were intraperitoneally challenged with lipopolysaccharide (LPS) followed by an intrahippocampal injection of histamine. We showed that histamine per se triggered glial reactivity and induced mild long-term impairments in neurogenesis, reducing immature neurons dendritic volume and complexity. Nevertheless, in mice exposed to LPS (2 mg/Kg), histamine was able to counteract LPS-induced glial activation and release of pro-inflammatory molecules as well as neurogenesis impairment. Moreover, histamine prevented LPS-induced loss of immature neurons complexity as well as LPS-induced loss of both CREB and PSD-95 proteins (essential for proper neuronal activity). Altogether, our results highlight histamine as a potential therapeutic agent to treat neurological conditions associated with hippocampal neuroinflammation and neurodegeneration.
Highlights
Histamine is an endogenous biogenic amine classically associated with peripheral allergic and inflammatory reactions but it can regulate both brain inflammation[1] and neurogenesis[2,3]
To identify the role of histamine in hippocampal inflammation we assessed by western blotting the levels of glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba-1) proteins to correlate with the levels of activated astrocytes and microglia, respectively, as well as the expression of the inflammatory mediators IL-1β and high mobility group box 1 protein (HMGB1) in LPS-challenged mice treated or not with histamine (Fig. 1)
We observed that histamine per se significantly increased the reactivity of astrocytes (GFAP: PBS 100.0 ± 15.9, His 161.7 ± 8.8, n = 5–6, F = 4.016, P = 0.0126; Fig. 1B) and tended to increase the reactivity of microglia (Iba-1: PBS 100.0 ± 15.9, His 186.7 ± 20.3, n = 7, F = 4.226, P = 0.0716; Fig. 1C)
Summary
Histamine is an endogenous biogenic amine classically associated with peripheral allergic and inflammatory reactions but it can regulate both brain inflammation[1] and neurogenesis[2,3]. It was recently demonstrated that initial peripheral inflammatory stimuli, such as LPS, generates immune memory in brain macrophages (microglia) resulting in a differential immune response to subsequent stimuli[10] This immune memory contributes to the modulation of several neurological pathologies and might explain the dual role of histamine. There is a lack of information regarding the effects of increased histamine levels in the hippocampus, a brain region that plays a key role in behavior and cognitive performance and that is compromised under neuroinflammatory conditions In this sense, we evaluated the effects of histamine per se or under an inflammatory context mimicked by LPS in both hippocampal neuroinflammation and neurogenesis in adult mice. We validate histamine as a potential therapeutic molecule in the fight against neuroinflammatory conditions
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