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MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/β-Catenin Signaling in Parkinsonian Rats.
ACS Chem Neurosci. 2017 03 15; 8(3):592-605.AC

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+Show Affiliations

Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI) , BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI) , BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI) , BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.Pharmacology Division, CSIR-Central Drug Research Institute (CSIR-CDRI) , BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27977132

Citation

Singh, Sonu, et al. "MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms Via Wnt/β-Catenin Signaling in Parkinsonian Rats." ACS Chemical Neuroscience, vol. 8, no. 3, 2017, pp. 592-605.
Singh S, Mishra A, Srivastava N, et al. MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/β-Catenin Signaling in Parkinsonian Rats. ACS Chem Neurosci. 2017;8(3):592-605.
Singh, S., Mishra, A., Srivastava, N., & Shukla, S. (2017). MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/β-Catenin Signaling in Parkinsonian Rats. ACS Chemical Neuroscience, 8(3), 592-605. https://doi.org/10.1021/acschemneuro.6b00354
Singh S, et al. MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms Via Wnt/β-Catenin Signaling in Parkinsonian Rats. ACS Chem Neurosci. 2017 03 15;8(3):592-605. PubMed PMID: 27977132.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/β-Catenin Signaling in Parkinsonian Rats. AU - Singh,Sonu, AU - Mishra,Akanksha, AU - Srivastava,Neha, AU - Shukla,Shubha, Y1 - 2016/12/15/ PY - 2016/12/16/pubmed PY - 2017/10/27/medline PY - 2016/12/16/entrez KW - MK-801 KW - Parkinson’s disease KW - hippocampal neurogenesis KW - neural stem cells KW - nonmotor symptoms SP - 592 EP - 605 JF - ACS chemical neuroscience JO - ACS Chem Neurosci VL - 8 IS - 3 N2 - 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. SN - 1948-7193 UR - https://www.unboundmedicine.com/medline/citation/27977132/MK_801__Dizocilpine__Regulates_Multiple_Steps_of_Adult_Hippocampal_Neurogenesis_and_Alters_Psychological_Symptoms_via_Wnt/β_Catenin_Signaling_in_Parkinsonian_Rats_ L2 - https://doi.org/10.1021/acschemneuro.6b00354 DB - PRIME DP - Unbound Medicine ER -