title: MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/β-Catenin Signaling in Parkinsonian Rats.
abstract: 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-3β (GSK-3β) through up-regulation of Wnt-3a, which resulted in the activation of Wnt/β-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.
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI) , BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Sonu
authors.initials: S
authors.lastname: Singh
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI) , BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI) , BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Neha
authors.initials: N
authors.lastname: Srivastava
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI) , BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Shubha
authors.identifier: 0000-0002-2389-6685
authors.initials: S
authors.lastname: Shukla
mesh_terms: D000221:Adaptation, Ocular / Q000187:drug effects; D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D019964:Mood Disorders / Q000188:drug therapy* / Q000209:etiology; D009043:Motor Activity / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016627:Oxidopamine / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D019394:Ki-67 Antigen; D018696:Neuroprotective Agents; D051153:Wnt Proteins; D051176:beta Catenin; D016291:Dizocilpine Maleate; D016627:Oxidopamine
keywords: MK-801; Parkinson’s disease; hippocampal neurogenesis; neural stem cells; nonmotor symptoms