Motor and memory function in rat models of cyanide toxicity and vascular occlusion induced ischemic injury

Although oxidative stress is characteristic of global vascular occlusion and cyanide toxicity, the pattern of cerebral metabolism reconditioning and rate of progression or reversal of neural tissue damage differ for both forms of ischemia. Thus, it is important to compare cognitive and motor functions in both models of ischemia involving cyanide treatment (CN) and vascular occlusion (VO). Adult Wistar rats (N = 30) were divided into three groups; VO (n = 12), CN (n = 12) and Control-CO (n = 6). The CN was treated with 30 mg/Kg of potassium cyanide (KCN); VO was subjected to global vascular occlusion-both for duration of 10 days. The control (CO) was fed on normal rat chow and water for the same duration. At day 10, the test and control groups (CN, VO and CO) were subjected to motor function tests (Table edge tests and Open Field Test) and memory function tests (Y-Maze and Novel object recognition) while the withdrawal groups CN-I and VO-I were subjected to the same set of tests at day 20 (the withdrawal phase). The results show that both cyanide toxicity and vascular occlusion caused a decline in motor and memory function when compared with the control. Also, the cyanide treatment produced a more rapid decline in these behavioral parameters when compared with the vascular occlusion during the treatment phase. After the withdrawal phase, cyanide treatment (CN-I) showed either an improvement or restoration of motor and memory function when compared to the CN and control. Withdrawal of vascular occlusion caused no improvement, and in some cases a decline in motor and memory function. In conclusion, cyanide toxicity caused a decline in motor and memory function after the treatment while vascular occlusion caused no significant decline in cognition and motor function at this time. After the withdrawal phase, the effect of cyanide toxicity was reduced and significant improvements were observed in the behavioral tests (motor and cognitive), while a decline in these functions were seen in the vascular occlusion group after this phase. © 2014 Elsevier Ireland Ltd. All rights reserved

Vitamin D3 Receptor Activation Rescued Corticostriatal Neural Activity and Improved Motor-Cognitive Function in −D2R Parkinsonian Mice Model

Background: fourth generation antipsychotics have been implicated in the blockade of calcium signalling through inhibition of dopamine receptive sites on dopaminergic D2 Receptor (D2R). As a result of the abnormal calcium signalling associated with D2R inhibition, changes occur in the motor and memory neural axis leading to the observed behavioural deficits after prolonged haloperidol. Thus, Vitamin D3 receptor (VD3R), a calcium controlling receptor in the striatum can be targeted to relief the neurological symptoms associated with haloperidol (−D2R) induced PD. Aim: This study sets to investigate the role of VD3R activation in vitro and in vivo after haloperidolinduced Dopaminergic (D2R) blockade. In addition, we examined the associated neural activity and behavioural changes in parkinsonian and VDRA intervention mice. Methods: Dopaminergic D2R inhibition was investigated in vitro using Melanocytes isolated from the scale of a Tilapia. In four separate set ups, the cells were cultured in calcium free Ringer’s solution as follows; 300 μM haloperidol, 100 μM VD3, 100 mM calcium chloride and a combination of 300 μM haloperidol and 100 μM VD3. Subsequently, dopaminergic vesicle accumulation and calcium signalling were observed in bright field microscopy using blue and green fluorescence probes. In the second phase, PD was induced in adult BALB/c mice (−D2; n = 8) after 14 days of intraperitoneal haloperidol treatment (10 mg/Kg). A set of n = 4 mice were untreated (−D2) while the other group (n = 4) received 100 mg/Kg of VD3 for 7 days (−D2/+VDR). The control groups (n = 4 each) were treated with normal saline (NS) and VD3 (+VDR) for 14 days. At the end of the treatment phase, the animals were assessed in Rotarod, parallel bar-, cylinder-, Y-Maze-, one trial place recognition- and novel object recognition-(NOR) tests. Neural activity was measured using chronic electrode implants placed in the M1 (motor cortex), CPu (striatum), CA1 (hippocampus) and PFC (prefrontal cortex). Neural activity was compared with the outcomes of behavioural tests for memory and motor functions and data was expressed as mean ± SEM (analysed using ANOVA with Tukey post-hoc test, significant level was set at 0.05). Results/Discussion: in vitro outcomes show that VDR increase calcium signalling and reverses the effect of haloperidol; specifically by reducing dopaminergic vesicle accumulation in the cell body. Similarly, in vivo neural recordings suggest an increase in calcium hyperpolarization currents in the CPu and PFC of intervention mice (−D2/+VDR) when compared with the parkinsonian mice (−D2). These animals (−D2/+VDR) also recorded an improvement in spatial working memory and motor function versus the Parkinsonian mice (−D2). These outcomes suggest the role of CPu-PFC corticostriatal outputs in the motor-cognitive decline seen in parkinsonian mice. Similarly, VDRA reduced the neural deficits through restoration of calcium currents (burst activities) in the intervention mice (−D2/+VDR). Conclusion: VDRA treatment reduced the motor-cognitive defects observed in haloperidol induced PD. Our findings suggest the role of VDRA in restoration of calcium currents associated with PFC and CPu corticostriatal outputs seen as burst frequencies in in vivo neural recording

Vitamin D 3 Receptor Activation Rescued Corticostriatal Neural Activity and Improved Motor Function in –D 2 R Tardive Dyskinesia Mice Model

Haloperidol-induced dyskinesia has been linked to a reduction in dopamine activity characterized by the inhibition of dopamine receptive sites on D2-receptor (D2R). As a result of D2R inhibition, calcium-linked neural activity is affected and seen as a decline in motor-cognitive function after prolonged haloperidol use in the treatment of psychotic disorders. In this study, we have elucidated the relationship between haloperidol-induced tardive dyskinesia and the neural activity in motor cortex (M1), basal nucleus (CPu), prefrontal cortex (PFC) and hippocampus (CA1). Also, we explored the role of Vitamin D3 receptor (VD3R) activation as a therapeutic target in improving motor-cognitive functions in dyskinetic mice. Dyskinesia was induced in adult BALB/c mice after 28 days of haloperidol treatment (10 mg/Kg; intraperitoneal). We established the presence of abnormal involuntary movements (AIMs) in the haloperidol treated mice (−D2) through assessment of the threshold and amplitude of abnormal involuntary movements (AIMs) for the Limbs (Li) and Orolingual (Ol) area (Li and Ol AIMs). As a confirmatory test, the dyskinetic mice (−D2) showed high global AIMs score when compared with the VD3RA intervention group (−D2/+VDR) for Li and Ol AIMs. Furthermore, in the behavioral tests, the dyskinetic mice exhibited a decrease in latency of fall (LOF; Rotarod-P < 0.05), climbing attempts (Cylinder test; P < 0.05) and latency of Turning (Parallel bar test; LOT-P < 0.05) when compared with the control. The reduced motor function in dyskinetic mice was associated with a decline in CPu-CA1 burst frequencies and an increase in M1-PFC cortical activity. However, after VD3RA intervention (−D2/+VDR), 100 mg/Kg for 7 days, CPu-CA1 burst activity was restored leading to a decrease in abnormal movement, and an increase in motor function. Ultimately, we deduced that VD3RA activation reduced the threshold of abnormal movement in haloperidol induced dyskinesia

Vitamin D 3 Receptor Activation Rescued Corticostriatal Neural Activity and Improved Motor - Cognitive Function in − D 2 R Parkinsonian Mice Model

fourth generation antipsychotics have been implicated in the blockade of calcium signalling through inhibition of dopamine receptive sites on dopaminergic D 2 Receptor (D 2 R). As a result of the abnormal calcium signalling associated with D 2 R inhibition, changes occur in the m o- tor and memory neural axis leading to the observed behavioural deficits after prolonged halope r- idol. Thus, Vitamin D 3 receptor (VD 3 R), a calcium controlling receptor in the striatum can be ta r- geted to relief the neurological symptoms associated with haloperidol ( − D 2 R) induced PD. Aim: This study sets to investigate the role of VD3R activation in vitro and in vivo after haloperidol - induced Dopaminergic (D 2 R) blockade. In addi tion, we examined the associated neural activity and behavioural changes in parkinsonian and VDRA intervention mice. Methods: Dopaminergic D 2 R inhibition was investigated in vitro using Melanocytes isolated from the scale of a Tilapia. In four separate set ups, the cells were cultured in calcium free Ringer’s solution as follows; 300 μM haloperidol, 100 μM VD 3 , 100 mM calcium chloride and a combination of 300 μM haloperidol and 100 μM VD 3 . Subsequently, dopaminergic vesicle accumulation and calcium signalling were observed in bright field microscopy using blue and green fluorescence probes. In the second phase, PD was induced in adult BALB/c mice ( − D 2 ; n = 8) after 14 days of intraperitoneal haloperidol treatment (10 mg/Kg). A set of n = 4 mice were untreated ( − D 2 ) while the other group (n = 4) r e- ceived 100 mg/Kg of VD 3 for 7 days ( − D 2 /+VDR). The control groups (n = 4 each) were treated with normal saline (NS) and VD 3 (+VDR) fo r 14 days. At the end of the treatment phase, the animals were assessed in Rotarod, parallel bar - , cylinder - , Y - Maze - , one trial place recognition - and novel object recognition - (NOR) tests. Neural activity was measured using chronic electrode implants plac ed in the M1 (motor cortex), CPu (striatum), CA1 (hippocampus) and PFC (prefrontal cortex). Neural activity was compared with the outcomes of behavioural tests for memory and motor fun c- tions and data was expressed as mean ± SEM (analysed using ANOVA with T ukey post - hoc test, significant level was set at 0.05). Results/Discussion: in vitro outcomes show that VDR increase calcium signalling and reverses the effect of haloperidol; specifically by reducing dopaminergic vesicle accumulation in the cell body. Sim ilarly, in vivo neural recordings suggest an increase in calcium hyperpolarization currents in the CPu and PFC of intervention mice ( − D 2 /+VDR) when compared with the parkinsonian mice ( − D 2 ). These animals ( − D 2 /+VDR) also recorded an i m- provement in spatial working memory and motor function versus the Parkinsonian mice ( − D 2 ). These outcomes suggest the role of CPu - PFC corticostriatal outputs in the motor - cognitive decline seen in parkinsonian mice. Similarly, VDRA reduced the neural deficits through restorati on of ca l- cium currents (burst activities) in the intervention mice ( − D 2 /+VDR). Conclusion: VDRA treatment reduced the motor - cognitive defects observed in haloperidol induced PD. Our findings suggest the role of VDRA in restoration of calcium currents assoc iated with PFC and CPu corticostriatal ou t- puts seen as burst frequencies in in vivo neural recording

−NMDA R/+VDR pharmacological phenotype as a novel therapeutic target in relieving motor–cognitive impairments in Parkinsonism

<div><p></p><p><i>Background</i>: 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</p><p>.<i>Aim</i>: 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 <i>in vivo.</i></p><p><i>Methods</i>: Adult mice were separated into six groups of <i>n</i> = 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 <i>in vivo</i> 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.</p><p><i>Result/Discussion</i>: 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.</p><p><i>Conclusion</i>: 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.</p></div