title: -NMDA R/+VDR pharmacological phenotype as a novel therapeutic target in relieving motor-cognitive impairments in Parkinsonism.
abstract: BACKGROUND
  Parkinsonism describes Parkinson's disease and other associated degenerative changes in the brain resulting in movement disorders. The motor cortex, extrapyramidal tracts and nigrostriatal tract are brain regions forming part of the motor neural system and are primary targets for drug or chemotoxins induced Parkinsonism. The cause of Parkinsonism has been described as wide and elusive, however, environmental toxins and drugs accounts for large percentage of spontaneous cases in humans. A common mechanism in the cause and progression of drug/chemotoxin induced Parkinsonism involves calcium signalling in; oxidative stress, autophagy, cytoskeletal instability and excitotoxicity .
  
  
  OBJECTIVE
  This study sets to investigate the effect of targeting calcium controlling receptors, specifically activation of Vitamin D3 receptor (VDR) and inhibition of N-Methyl-D-Aspartate Receptor (NMDAR) in the motor cortex of mice model of drug induced Parkinsonism. Also we demonstrated how these interventions improved neural activity, cytoskeleton, glia/neuron count and motor-cognitive functions in vivo.
  
  
  METHODS
  Adult mice were separated into six groups of n = 5 animals each. Body weight (5 mg/kg) of haloperidol was administered intraperitoneally for 7 days to block dopaminergic D2 receptors and induce degeneration in the motor cortex following which an intervention of VDR agonist (VDRA), and (or) NMDAR inhibitor was administered for 7 days. A set of control animals received normal saline while a separate group of control animals received the combined intervention of VDRA and NMDAR inhibitor without prior treatment with haloperidol. Behavioral tests for motor and cognitive functions were carried out at the end of the treatment and intervention periods. Subsequently, neural activity in the motor cortex was recorded in vivo using unilateral wire electrodes. We also employed immunohistochemistry to demonstrate neuron, glia, neurofilament and proliferation in the motor cortex after haloperidol treatment and the intervention.
  
  
  CONCLUSIONS
  We observed a decline in motor function and memory index in the haloperidol treatment group when compared with the control. Similarly, there was a decline in neural activity in the motor cortex (a reduced depolarization peak frequency). General cell loss (neuron and glia) and depletion of neurofilament were characteristic anatomical changes seen in the motor cortex of this group. However, Vitamin D3 intervention facilitated an improvement in motor-cognitive function, neural activity, glia/neuron survival and neurofilament expression. NMDAR inhibition and the combined intervention improved motor-cognitive functions but not as significant as values observed in VDRA intervention. Interestingly, animals treated with the combined intervention without prior haloperidol treatment showed a decline in motor function and neural activity.
  
  
  CONCLUSIONS
  Our findings suggest that calcium mediated toxicity is primary to the cause and progression of Parkinsonism and targeting receptors that primarily modulates calcium reduces the morphological and behavioral deficits in drug induced Parkinsonism. VDR activation was more effective than NMDAR inhibition and a combined intervention. We conclude that targeting VDR is key for controlling calcium toxicity in drug/chemotoxin induced Parkinsonism.
authors.affiliation: a Department of Anatomy , College of Medicine and Health Sciences, Afe Babalola University , Ekiti State Ado-Ekiti , Nigeria .
authors.forename: Olalekan Michael
authors.initials: OM
authors.lastname: Ogundele
authors.affiliation: a Department of Anatomy , College of Medicine and Health Sciences, Afe Babalola University , Ekiti State Ado-Ekiti , Nigeria .
authors.forename: Ednar Tarebi
authors.initials: ET
authors.lastname: Nanakumo
authors.affiliation: b Department of Anatomy , College of Health Sciences, University of Ilorin , Ilorin , Kwara State , Nigeria .
authors.forename: Azeez Olakunle
authors.initials: AO
authors.lastname: Ishola
authors.affiliation: c Department of Mathematical and Physical Sciences , College of Sciences, Afe Babalola University , Ado-Ekiti , Ekiti State , Nigeria , and.
authors.forename: Oluwafemi Michael
authors.initials: OM
authors.lastname: Obende
authors.affiliation: a Department of Anatomy , College of Medicine and Health Sciences, Afe Babalola University , Ekiti State Ado-Ekiti , Nigeria .
authors.forename: Linus Anderson
authors.initials: LA
authors.lastname: Enye
authors.affiliation: b Department of Anatomy , College of Health Sciences, University of Ilorin , Ilorin , Kwara State , Nigeria .
authors.forename: Wasiu Gbolahan
authors.initials: WG
authors.lastname: Balogun
authors.affiliation: b Department of Anatomy , College of Health Sciences, University of Ilorin , Ilorin , Kwara State , Nigeria .
authors.forename: Ansa Emmanuel
authors.initials: AE
authors.lastname: Cobham
authors.affiliation: d Department of Physiology , College of Health Sciences, University of Ilorin , Ilorin , Kwara State , Nigeria.
authors.forename: Amin
authors.initials: A
authors.lastname: Abdulbasit
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001921:Brain / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D009044:Motor Cortex / Q000187:drug effects / Q000503:physiopathology; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology; D010641:Phenotype; D018167:Receptors, Calcitriol / Q000819:agonists / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D018167:Receptors, Calcitriol; D016194:Receptors, N-Methyl-D-Aspartate; D006220:Haloperidol; D002118:Calcium
keywords: Calcium; NMDAR; VDR; cell death; degeneration; haldol; parkinsonism