The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization

Írisz Szabó, Orsolya M. Tóth, Zsolt Török, Dániel Péter Varga, Ákos Menyhárt, Rita Frank, Dóra Hantosi, Ákos Hunya, Ferenc Bari, Ibolya Horváth, László Vigh, Eszter Farkas

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Abstract

Background and Purpose: A new class of dihydropyridine derivatives, which act as co-inducers of heat shock protein but are devoid of calcium channel antagonist and vasodilator effects, has recently been developed with the purpose of selectively targeting neurodegeneration. Here, we evaluated the action of one of these novel compounds LA1011 on neurovascular coupling in the ischaemic rat cerebral cortex. As a reference, we applied nimodipine, a vasodilator dihydropyridine and well-known calcium channel antagonist. Experimental Approach: Rats were treated with LA1011 or nimodipine, either by chronic, systemic (LA1011), or acute, local administration (LA1011 and nimodipine). In the latter treatment group, global forebrain ischaemia was induced in half of the animals by bilateral common carotid artery occlusion under isoflurane anaesthesia. Functional hyperaemia in the somatosensory cortex was created by mechanical stimulation of the contralateral whisker pad under α-chloralose anaesthesia. Spreading depolarization (SD) events were elicited subsequently by 1 M KCl. Local field potential and cerebral blood flow (CBF) in the parietal somatosensory cortex were monitored by electrophysiology and laser Doppler flowmetry. Key Results: LA1011 did not alter CBF, but intensified SD, presumably indicating the co-induction of heat shock proteins, and, perhaps an anti-inflammatory effect. Nimodipine attenuated evoked potentials and SD. In addition to the elevation of baseline CBF, nimodipine augmented hyperaemia in response to both somatosensory stimulation and SD, particularly under ischaemia. Conclusions and implications: In contrast to the CBF improvement achieved with nimodipine, LA1011 seems not to have discernible cerebrovascular effects but may up-regulate the stress response.

Original languageEnglish
Pages (from-to)1222-1234
Number of pages13
JournalBritish journal of pharmacology
Volume176
Issue number9
DOIs
Publication statusPublished - May 2019

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ASJC Scopus subject areas

  • Pharmacology

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