Clemastine Alleviates Depressive-Like Behavior Through Reversing the Imbalance of Microglia-Related Pro-inflammatory State in Mouse Hippocampus

Abstract

Backgrounds: Abundant reports indicate that neuroinflammatory signaling contributes to behavioral complications associated with depression and may be related to treatment response. The glial cells, especially microglia and astrocytes in brain regions of hippocampus and medial prefrontal cortex (mPFC), are major components of CNS innate immunity. Moreover, purinergic receptor P2X, ligand-gated ion channel 7 (P2X7R) was recently reckoned as a pivotal regulator in central immune system. Besides, it was pointed out that clemastine, a first-generation histamine receptor H1 (HRH1) antagonist with considerable safety profile and pharmacological effect, may suppress immune activation through modulating P2X7R. Herein, we investigated the potential anti-neuroinflammatory effects of clemastine on chronic unpredictable mild stress (CUMS)-induced depressive-like behavior in a mouse model.Methods: Male BALB/c mice were subjected to CUMS for 4 weeks, some of them were injected with clemastine fumarate solution. After the stress procedure, behavioral tests including Sucrose Preference Tests (SPTs), Tail Suspension Tests (TSTs) and locomotor activities were performed to evaluate depressive-like phenotype. Subsequently, expression of cytokines and microglia-related inflammatory biomarkers were assessed.Results: In the present research, we found that clemastine significantly reversed both the declination of SPT percentage and the extension of TST immobility durations in depression mouse model without affecting locomotor activity. Also, we observed that clemastine regulated the imbalance of pro-inflammatory cytokines including interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) in the hippocampus and serum of depressive-like mice. Additionally, clemastine significantly suppressed microglial M1-like activation specifically in the hippocampus, and also improved hippocampal astrocytic loss. Furthermore, clemastine downregulated hippocampal P2X7R without interfering with the expression of HRH1.Conclusion: As a safe and efficient anti-allergic agent, clemastine could impressively alleviate stress-related depressive-like phenotype in mice. Further evidence supported that it was because of the potential function of clemastine in modulating the expression of P2X7 receptor possibly independent of HRH1, therefore suppressing the microglial M1-like activation and pro-inflammatory cytokines release in brain regions of hippocampus rather than mPFC.

Clemastine improves hypomyelination in rats with hypoxic–ischemic brain injury by reducing microglia-derived IL-1β via P38 signaling pathway

“…Furthermore, clemastine and MCC950 could reduce the excessive expression levels of NLRP3 and IL-1β, suggesting that clemastine and MCC950 featured an anti-inflammatory effect. Clemastine can inhibit the secretion of IL-1β by microglial cells [16], but the specific mechanism is unknown. According to reports, p38 is a signaling pathway regulating the IL-1β release [19].…”

“…Clemastine is a first-generation histamine H1 receptor (HH1R) antagonist with good safety that features antiinflammatory effects and improves oligodendrocyte differentiation in hypoxic brain injury [14]. This drug also enhances myelination, rescues behavioral changes, and regulates the imbalance of pro-inflammatory cytokines including IL-1β [15,16]. Extracellular signal-regulated kinase (ERK) signaling pathway was found to induce OPC maturation [17], and the activation of the former enhances the differentiation of the latter [18].…”

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

“…The selective P2X7R antagonist Brilliant Blue G (BBG) attenuated the increase of immobility time in TST and FST in mice after activation of the inflammasome by LPS (Ma et al, 2014). Similarly, BBG reversed the behavioral deterioration induced by UCMS in mice (Farooq et al, 2018), and clemastine, a nonselective antagonist of P2X7Rs, counteracted the prolonged duration of immobility in TST (Su et al, 2018).…”

Transcutaneous auricular vagal nerve stimulation inhibits P2X7R expression in limbic brain regions and reverses depression-like behavior in Zucker diabetic fatty rats

“…The results acquired from animal models have provided valuable information regarding the role of P2 × 7R in depressive disorders and stress responses. For example, mice exposed to chronic unpredictable mild stress (CUMS) have increased P2 × 7R expression in the medial prefrontal cortex and the hippocampus [19], and increased hippocampal P2 × 7R levels of mice disclosed to chronic restraint stress (CRS) were also recorded [20]. Moreover, clemastine [19] and ketamine [20] induces antidepressant-like effect, which was associated with downregulated hippocampal P2 × 7R expression in the in stressed mice.…”

“…For example, mice exposed to chronic unpredictable mild stress (CUMS) have increased P2 × 7R expression in the medial prefrontal cortex and the hippocampus [19], and increased hippocampal P2 × 7R levels of mice disclosed to chronic restraint stress (CRS) were also recorded [20]. Moreover, clemastine [19] and ketamine [20] induces antidepressant-like effect, which was associated with downregulated hippocampal P2 × 7R expression in the in stressed mice. Thus, it is worth investigating whether the depression-like behavior in ZDF rats is related to increased P2 × 7R expression in the central nervous system (CNS), which can further prove that whether ZDF rats are an excellent rodent model of depression.…”