Nimodipine reduces microglial activation in vitro as evidenced by morphological phenotype, phagocytic activity and high-throughput RNA sequencing

Pesti, István and Varga, Valentin and Qorri, Erda and Frank, Rita and Kata, Diána and Vinga, Krisztián and Szarvas, Péter and Menyhárt, Ákos and Gulya, Károly and Bari, Ferenc and Farkas, Eszter (2025) Nimodipine reduces microglial activation in vitro as evidenced by morphological phenotype, phagocytic activity and high-throughput RNA sequencing. BRITISH JOURNAL OF PHARMACOLOGY. ISSN 0007-1188 (Submitted)

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Abstract

Background and Purpose Nimodipine, an L-type voltage-gated calcium channel blocker, is an approved cerebral vasorelaxant. We hypothesize that nimodipine attenuates the pro-inflammatory shift in microglial phenotype. Here we analysed the effects of nimodipine on morphological and functional microglial phenotypes as well as their transcriptomic profile. Experimental Approach Live brain slice preparations from C57BL/6 mice and primary microglia cultures from neonatal Sprague Dawley rats were used. Microglia were activated by ischemia or lipopolysaccharide (LPS), and preparations were treated with nimodipine (5-10-20 μM). Microglial morphological phenotype, phagocytic activity, Iba1 expression and TNFα levels were evaluated. Total RNA was isolated from monocultures and processed for next generation RNA sequencing. Key Results LPS resulted in a pro-inflammatory microglial phenotype, affecting the expression of cytokines, the complement system and phagocytosis-related genes. LPS increased the transcription of ionotropic purinergic and some TRP channels but decreased the expression of voltage- and ligand-gated calcium channels, downregulated the expression of Ryr and IP3 receptors and increased transcription of the SERCA calcium pump. Nimodipine suppressed the ameboid morphological transformation and phagocytosis and altered the expression of 110 genes in the opposite direction to LPS activation, of which at least 20 were associated with microglial immune response, 7 with cell adhesion and 2 with autophagy regulation. Conclusion and Implications The effect of nimodipine goes beyond cerebral vasorelaxation. Nimodipine attenuates microglial activation by modulating Ca2+-dependent gene expression involved in intracellular signalling cascades to drive microglial immune responses. Consideration should be given to expanding the medical field of indication of nimodipine.

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