MMSL 2019, 88(4):166-179 | DOI: 10.31482/mmsl.2019.019

PHARMACOLOGICAL PROFILE OF DIZOCILPINE (MK-801) AND ITS POTENTIAL USE IN ANIMAL MODEL OF SCHIZOPHRENIAReview article

Jan Konečný ORCID...1,2, Radomír Jůza ORCID...3, Ondřej Soukup ORCID...1,2, Jan Korábečný ORCID...1,2,3*
1 Katedra toxikologie a vojenské farmacie, Fakulta vojenského zdravotnictví, Třebešská 1575, 500 02, Hradec Králové, Česká republika
2 Centrum biomedicínského výzkumu, Fakultní nemocnice Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Česká republika
3 Národní ústav duševního zdraví, Topolová 748, 250 67 Klecany, Česká republika

N-Methyl-D-aspartátový (NMDA) receptor patří do skupiny glutamátových receptorů, které se dále dělí na ionotropní a metabotropní. V CNS má vliv na synaptickou plasticitu a rozvoj neuronálních synapsí. Ionotropní NMDA receptory jsou aktivovány glutamátem, díky čemuž proudí pozitivně nabité ionty skrz membránu po svém koncentračním gradientu. Nicméně nadměrné hladiny glutamátu působí excitotoxicky díky vysokým intracelulárním hladinám Ca2+ a mohou vést k buněčné smrti neuronů pozorované např. u neurodegenerativních onemocnění. Antagonisté NMDA receptorů, mezi které patří například dizocilpin, ovlivňují prostupnost NMDA receptoru a zamezují tak vstupu iontů Ca2+ do buňky. Dizocilpin působí jako nekompetitivní antagonista NMDA receptoru, má antikonvulzivní a anestetické účinky. Jeho terapeutické použití u lidí není vhodné z důvodu výskytu četných vedlejších účinků, experimentálně je však využíván jako farmakologicky indukovaný animální model schizofrenie.

Keywords: dizocilpin; MK-801; NMDA; schizofrenie; antipsychotika

N-Methyl-D-aspartate (NMDA) receptor belongs to the group of glutamate receptors, which are further divided into ionotropic and metabotropic. It affects synaptic plasticity and the development of neuronal synapsis in CNS. Ionotropic NMDA receptors are activated by glutamate, thereby flowing positively charged ions through the membrane along its concentration gradient. However, glutamate overload leads to excitotoxicity, due to high levels of Ca2+, which leads to cell death assocciated with neurodegenerative diseases. NMDA antagonists like dizocilpine reduce intracellular concentration of Ca2+ by modulating permeability of NMDA receptor channel. Dizocilpine act as a non-competitive NMDA receptor antagonist with anticonvulsant and anesthetic properties. Its therapeutic use in humans is limited due its numerous side effects, but it is experimentally used as an animal model of schizophrenia.

Keywords: dizocilpine; MK-801; NMDA; schizophrenia; antipsychotics

Received: July 19, 2019; Accepted: September 5, 2019; Prepublished online: September 18, 2019; Published: December 6, 2019  Show citation

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Konečný, J., Jůza, R., Soukup, O., & Korábečný, J. (2019). PHARMACOLOGICAL PROFILE OF DIZOCILPINE (MK-801) AND ITS POTENTIAL USE IN ANIMAL MODEL OF SCHIZOPHRENIA. MMSL, 88(4), 166-179. doi: 10.31482/mmsl.2019.019
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