K channel blockage with 3,4-diaminopyridine potentiates the effect of L-DOPA on dopamine release in striatal slices prep
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RESEARCH ARTICLE
K channel blockage with 3,4‑diaminopyridine potentiates the effect of L‑DOPA on dopamine release in striatal slices prepared from 6‑OHDA pre‑treated rats Zulfiye Gul1 · Gozde Duyu2 · Burcin Altinbas3 · R. Levent Buyukuysal4 Received: 1 July 2020 / Accepted: 24 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Although L-DOPA revolutionized in the treatment of Parkinson’s disease, most patients developed motor complications after several years of treatment. Adjunctive therapy to L-DOPA with drugs related to dopaminergic signaling may reduce its dose without decreasing the therapeutic efficiency and thus ameliorates its adverse effects. It has been shown that 3,4-diaminopyridine (3,4-DAP), a K channel blocker, increased dopamine release from striatal slices by increasing neuronal firing in striatal dopaminergic terminals. The current study investigates whether 3,4-DAP may enhance L-DOPA-induced dopamine (DA) release from striatal slices by increasing neuronal firing in striatal dopaminergic terminals. The effects of L-DOPA and 3,4-DAP on spontaneous DA and DOPAC release were tested in vitro, on acute rat striatal slices prepared from non-treated and 6-hydroxydopamine-pre-treated rats. DA and DOPAC levels were determined by HPLC methods. When 3,4-diaminopyridine was combined with L-DOPA, the observed effect was considerably greater than the increases induced by L-DOPA or 3,4-DAP alone in normoxic and neurodegenerative conditions produced by FeSO4 and 6-hydroxydopamine. Furthermore, L-DOPA plus 3,4-DAP also ameliorated DOPAC levels in neurodegenerative conditions. These data indicate that 3,4 DAP plus L-DOPA activates striatal dopaminergic terminals by increasing the DA release and, thus, could be considered as a promising finding in treatment of acute and chronic injury in dopaminergic neurons. Keywords Dopamine · 3,4 DAP · K channel blocker · L-DOPA · Parkinson disease
Introduction Parkinson’s disease (PD) is a common, progressive neurodegenerative disease that has affected 6.2 million people from 1990 to 2015 (GBD 2015 Neurological Disorders Collaborator Group 2017) and this number is estimated to over 12 million by 2040 (Dorsey and Bloem 2018). It is characterized by Communicated by Bill J Yates. * Zulfiye Gul [email protected] 1
Department of Medical Pharmacology, Faculty of Medicine, Bahcesehir University, Istanbul 34743, Turkey
2
Faculty of Medicine, Bahcesehir University, Istanbul 34743, Turkey
3
Department of Physiology, Faculty of Medicine, Sanko University, Gaziantep 27090, Turkey
4
Department of Medical Pharmacology, Faculty of Medicine, Uludag University, Bursa 16059, Turkey
bradykinesia, tremor, and rigidity, and diagnosed as a result of degeneration of 60% of nigral dopaminergic neurons and loss of 60–70% of striatal Dopamine (DA) levels (Dauer and Przedborski 2003). Although levodopa (L-DOPA) is still the most effective treatment of PD for more than 60 years, patients suffer from L-DOPA-induced dyskinesia and motor fluctuat
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