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Nimodipine Activates TrkB Neurotrophin Receptors and Induces Neuroplastic and Neuroprotective Signaling Events in the Mouse Hippocampus and Prefrontal Cortex

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Abstract

The L-type calcium channel blocker nimodipine improves clinical outcome produced by delayed cortical ischemia or vasospasm associated with subarachnoid hemorrhage. While vasoactive mechanisms are strongly implicated in these therapeutic actions of nimodipine, we sought to test whether nimodipine might also regulate neurotrophic and neuroplastic signaling events associated with TrkB neurotrophin receptor activation. Adult male mice were acutely treated with vehicle or nimodipine (10 mg/kg, s.c., 1.5 h) after which the phosphorylation states of TrkB, cyclic-AMP response element binding protein (CREB), protein kinase B (Akt), extracellular regulated kinase (ERK), mammalian target of rapamycin (mTor) and p70S6 kinase (p70S6k) from prefrontal cortex and hippocampus were assessed. Nimodipine increased the phosphorylation of the TrkB catalytic domain and the phosphoslipase-Cγ1 (PLCγ1) domain, whereas phosphorylation of the TrkB Shc binding site remained unaltered. Nimodipine-induced TrkB phosphorylation was associated with increased phosphorylation levels of Akt and CREB in the prefrontal cortex and the hippocampus whereas phosphorylation of ERK, mTor and p70S6k remained unaltered. Nimodipine-induced TrkB signaling was not associated with changes in BDNF mRNA or protein levels. These nimodipine-induced changes on TrkB signaling mimic those produced by antidepressant drugs and thus propose common mechanisms and long-term functional consequences for the effects of these medications. This work provides a strong basis for investigating the role of TrkB-associated signaling underlying the neuroprotective and neuroplastic effects of nimodipine in translationally relevant animal models of brain trauma or compromised synaptic plasticity.

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Acknowledgments

The authors would like to thank Outi Nikkilä and M.Sci. Hanna Antila for technical assistance. We thank Dr. Giuseppe Cortese for language editing.

Disclosure

E.C. is an advisor and shareholder in Herantis Pharma, Inc. E.C. and T.R. have received research support from Orion Pharma, Hermo Pharma and Ono Pharmaceuticals. J.K. has received funding from Maire Taponen foundation for completing thesis. N.M and J.U. have nothing to declare. All authors declare no financial conflict of interests related to this study.

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  1. Neuroscience Center, University of Helsinki, P.O. Box 56 (Viikinkaari 4), 00014, Helsinki, Finland

    Janne Koskimäki, Nobuaki Matsui, Juzoh Umemori, Tomi Rantamäki & Eero Castrén

  2. Faculty of Medicine, University of Turku, P.O.Box 52 (Kiinamyllynkatu 4-8), 20520, Turku, Finland

    Janne Koskimäki

  3. Department of Neurosurgery, Helsinki University Central Hospital, P.O. Box 266 (Topeliuksenkatu 5), 00029, Helsinki, Finland

    Janne Koskimäki

  4. Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiro-cho, Tokushima, 770-8514, Japan

    Nobuaki Matsui

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  1. Janne Koskimäki
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Correspondence to Eero Castrén.

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Janne Koskimäki and Nobuaki Matsui authors contributed equally to this work.

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Koskimäki, J., Matsui, N., Umemori, J. et al. Nimodipine Activates TrkB Neurotrophin Receptors and Induces Neuroplastic and Neuroprotective Signaling Events in the Mouse Hippocampus and Prefrontal Cortex. Cell Mol Neurobiol 35, 189–196 (2015). https://doi.org/10.1007/s10571-014-0110-5

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