MK-801 (Dizocilpine)

MK-801 (Dizocilpine) is a potent and selective antagonist of NMDA (N-methyl-D-aspartate) receptor (Ki = 30.5 nM). It acts as an open channel blocker for the NMDA receptor-operated ion channel. It is a drug implicated in central nervous system with anesthetic and anticonvulsant effect. [1]

NMDA receptor is a glutamate-gated cation channels that plays a vital role in regulating synaptic transmission, neuroplasticity and central nervous system development. It is involved in a range of physiological processes such as learning, memory and pain etc.

In vitro electrophysiological studies in the rat cortical-slice preparation, showed a potent, selective and noncompetitive antagonistic effect of MK 801 on depolarizing reaction to NMDA. [3] In mature cultures treated with dissolved 10 um MK-801 at 37 oC for 30 minutes, it exhibited attenuated apoptotic cell death. [2]

In rats with server permanent neurological deficits, MK-901 treatment improved neurological and histological outcome, and showed mild injury of neuronal necrosis.[4] Rodent administrated with up to 0.1 mg/kg MK801, exerted learning /memory impairment and cognitive dysfunctions. [5]

References:
[1] Kovacic P, Somanathan R.  Clinical physiology and mechanism of dizocilpine (MK-801): electron transfer, radicals, redox metabolites and bioactivity.  Oxid Med Cell Longev.  2010 Jan-Feb;3(1):13-22. doi: 10.4161/oxim.3.1.10028.
[2] Wise-Faberowski L, Pearlstein RD, Warner DS.  NMDA-induced apoptosis in mixed neuronal/glial cortical cell cultures: the effects of isoflurane and dizocilpine.  J Neurosurg Anesthesiol.  2006 Oct;18(4):240-6.
[3] Wong EH, Kemp JA, Priestley T, Knight AR, Woodruff GN, Iversen LL.  The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist.  Proc Natl Acad Sci U S A.  1986 Sep;83(18):7104-8.
[4] Kocaeli H, Korfali E, Oztürk H, Kahveci N, Yilmazlar S.  MK-801 improves neurological and histological outcomes after spinal cord ischemia induced by transient aortic cross-clipping in rats.  Surg Neurol. 2005;64 Suppl 2:S22-6; discussion S27. 
[5] van der Staay FJ, Rutten K, Erb C, Blokland A.  Effects of the cognition impairer MK-801 on learning and memory in mice and rats.  Behav Brain Res. 2011 Jun 20;220(1):215-29. 

Higher doses of (+)MK-801 (dizocilpine) induced mortality and procedural but not cognitive deficits in delayed testing in the active place avoidance with reversal on the Carousel.[Pubmed:25317686]

Physiol Res. 2015;64(2):269-75. Epub 2014 Oct 15.

Schizophrenia is a devastating disorder affecting 1 % of the world's population. An important role in the study of this disease is played by animal models. Since there is evidence that acute psychotic episodes can have consequences on later cognitive functioning, the present study has investigated the effects of a single systemic application of higher doses of (+)MK-801 (3 mg/kg and 5 mg/kg) to adult male Long-Evans rats from the Institute's breeding colony on delayed testing in the active place avoidance task with reversal on the Carousel (a rotating arena). Besides significant mortality due to the injections, a disruption of procedural functions in active place avoidance, after the dose 5 mg/kg was observed. It was concluded that Long-Evans rats from our breeding colony do not represent a suitable biomodel for studying the effects of single high-dose NMDA antagonists.

Dizocilpine (MK-801) impairs learning in the active place avoidance task but has no effect on the performance during task/context alternation.[Pubmed:26970577]

Behav Brain Res. 2016 May 15;305:247-57.

The prevention of engram interference, pattern separation, flexibility, cognitive coordination and spatial navigation are usually studied separately at the behavioral level. Impairment in executive functions is often observed in patients suffering from schizophrenia. We have designed a protocol for assessing these functions all together as behavioral separation. This protocol is based on alternated or sequential training in two tasks testing different hippocampal functions (the Morris water maze and active place avoidance), and alternated or sequential training in two similar environments of the active place avoidance task. In Experiment 1, we tested, in adult rats, whether the performance in two different spatial tasks was affected by their order in sequential learning, or by their day-to-day alternation. In Experiment 2, rats learned to solve the active place avoidance task in two environments either alternately or sequentially. We found that rats are able to acquire both tasks and to discriminate both similar contexts without obvious problems regardless of the order or the alternation. We used two groups of rats, controls and a rat model of psychosis induced by a subchronic intraperitoneal application of 0.08mg/kg of dizocilpine (MK-801), a non-competitive antagonist of NMDA receptors. Dizocilpine had no selective effect on parallel/sequential learning of tasks/contexts. However, it caused hyperlocomotion and a significant deficit in learning in the active place avoidance task regardless of the task alternation. Cognitive coordination tested by this task is probably more sensitive to dizocilpine than spatial orientation because no hyperactivity or learning impairment was observed in the Morris water maze.

Intracranial pancreatic islet transplantation increases islet hormone expression in the rat brain and attenuates behavioral dysfunctions induced by MK-801 (dizocilpine).[Pubmed:25943974]

Horm Behav. 2015 Jun;72:1-11.

The treatment of rodents with non-competitive antagonist of the N-Methyl-D-aspartate (NMDA) receptor, MK-801 (Dizocilpine), induces symptoms of psychosis, deficits in spatial memory and impairment of synaptic plasticity. Recent studies have suggested that insulin administration might attenuate the cognitive dysfunctions through the modulatory effect on the expression of NMDA receptors and on the brain insulin signaling. Intrahepatic pancreatic islet transplantation is known as an efficient tool for correcting impaired insulin signaling. We examined the capacity of syngeneic islets grafted into the cranial subarachnoid cavity to attenuate behavioral dysfunctions in rats exposed to MK-801. Animals were examined in the open field (OF) and the Morris Water Maze (MWM) tests following acute or subchronic administration of MK-801. We found well-vascularized grafted islets expressing insulin, glucagon and somatostatin onto the olfactory bulb and prefrontal cortex. Significantly higher levels of insulin were detected in the hippocampus and prefrontal cortex of transplanted animals compared to the non-transplanted rats. All animals expressed normal peripheral glucose homeostasis for two months after transplantation. OF tests revealed that rats exposed to MK-801 treatment, showed hyper-responsiveness in motility parameters and augmented center field exploration compared to intact controls and these effects were attenuated by the grafted islets. Moreover, in the MWM, the rats treated with MK-801 showed impairment of spatial memory that were partially corrected by the grafted islets. In conclusion, intracranial islet transplantation leads to the expression of islet hormones in the brain and attenuates behavioral and cognitive dysfunctions in rats exposed to MK-801 administration without altering the peripheral glucose homeostasis.

MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/beta-Catenin Signaling in Parkinsonian Rats.[Pubmed:27977132]

ACS Chem Neurosci. 2017 Mar 15;8(3):592-605.

Adult hippocampal neurogenesis is directly involved in regulation of stress, anxiety, and depression that are commonly observed nonmotor symptoms in Parkinson's disease (PD). These symptoms do not respond to pharmacological dopamine replacement therapy. Excitotoxic damage to neuronal cells by N-methyl-d-aspartate (NMDA) receptor activation is also a major contributing factor in PD development, but whether it regulates hippocampal neurogenesis and nonmotor symptoms in PD is yet unexplored. Herein, for the first time, we studied the effect of MK-801, an NMDA receptor antagonist, on adult hippocampal neurogenesis and behavioral functions in 6-OHDA (6-hydroxydopamine) induced rat model of PD. MK-801 treatment (0.2 mg/kg, ip) increased neural stem cell (NSC) proliferation, self-renewal capacity, long-term survival, and neuronal differentiation in the hippocampus of rat model of PD. MK-801 potentially enhanced long-term survival, improved dendritic arborization of immature neurons, and reduced 6-OHDA induced neurodegeneration via maintaining the NSC pool in hippocampus, leading to decreased anxiety and depression-like phenotypes in the PD model. MK-801 inhibited glycogen synthase kinase-3beta (GSK-3beta) through up-regulation of Wnt-3a, which resulted in the activation of Wnt/beta-catenin signaling leading to enhanced hippocampal neurogenesis in PD model. Additionally, MK-801 treatment protected the dopaminergic (DAergic) neurons in the nigrostriatal pathway and improved motor functions by increasing the expression of Nurr-1 and Pitx-3 in the PD model. Therefore, MK-801 treatment serves as a valuable tool to enhance hippocampal neurogenesis in PD, but further studies are needed to revisit the role of MK-801 in the neurodegenerative disorder before proposing a potential therapeutic candidate.

Dizocilpine (MK-801), a potent anticonvulsant, is a selective and non-competitive NMDA receptor antagonist, with a Kd of 37.2 nM in rat brain membranes. Dizocilpine acts by binding to a site located within the NMDA associated ion channel and thus prevents Ca2+ flux.

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