24 research outputs found
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
Pro-Neurogenic and Antioxidant Efficacy of Nigella sativa Oil Reduced Vulnerability Cholinesterase Dysfunction and Disruption in Amygdala-Dependent Behaviours in Chlorpyrifos Exposure
Background: Organophosphorus Pesticides (OPs) are
compounds with irreversible cholinesterase activity
which induce cholinergic neurotoxicity, but still remain
a widely used pesticide in household and agriculture.
Aim and Objectives: This study investigated the
efficacy of a natural antioxidant Nigella sativa Oil
(NSO) against Chlorpyrifos (CPF) induced oxidative
stress and implications on emotionality behaviours.
Material and Methods: Thirty-two adult Wistar rats
were randomly divided into four groups, and exposed
to (1 ml/kg b w) of normal saline, (14.9 mg/kg b w) of
CPF, (14.9 mg/kg b w) of CPF plus (1 ml/kg b w) of
NSO and (1 ml/kg b w) of NSO respectively for 14
consecutive days. Body weight were recorded at day 1
and 15 of the experiment, the rats were exposed to trials
in both Open Field Test (OFT) and Elevated Plus Maze
(EPM) to asses anxiety-like behaviours and fear related
learning respectively on the 13th day. Rats were
euthanized by the 15th day, the brains excised, and the
amygdala area of brains were removed, homogenized
to analyse for total Reactive Oxygen Species (ROS),
Nitrous Oxide (NO) levels and Acetylcholinesterase
(AChE) activities, while the other three were processed
for histology (Nissl stain) and Proliferative marker
(Ki67 immunohistochemistry). Results: Repeated CPF
exposure caused an increase in NO and ROS levels,
reduction in AChE activities and a loss in the
neurogenic cells in the amygdala. It was also a
prolonged freezing period, centre squares avoidance
and delayed transfer latency with CPF exposure.
However, NSO prevented the overproduction of ROS
and NO, and markedly reactivated AChE activities in
the amygdala either with or without CPF exposure.
NSO treatment was also, able to preserve neurogenic
cells in the amygdala and subsequently improved
amygdala-dependent behaviours in the treated rats.
Conclusion: The antioxidant efficacy of NSO could be
efficacious in CPF induced neuro-cognitive toxicity in
rats
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
Dichlorvos Induced AChE Inhibition in Discrete Brain Regions and the Neuro-Cognitive Implications: Ameliorative Effect of Nigella Sativa
Background: There has been a rise in accidental poisoning cases resulting from the indiscriminate use and exposure to Dichlorvos (DDVP), especially in developing countries, and no antidote with satisfactory efficacy is currently available. Thus, we investigated the AChE reactivation potential of Nigella sativa oil (NSO) following DDVP induced AChE inhibition patterns in the brain and the associated cognitive implications.
Methods: Fourty Wistar rats were randomly divided into four groups of 10 each.; The controls were administered PBS (1 ml/kg); DDVP (8.8 mg/kg) was given to the experimental group I; while DDVP+NSO (8.8 mg/kg + 1 ml/kg) and NSO (1 ml/kg) was administered orally to the experimental groups II and III respectively. All treatments lasted for 14 consecutive days. Morris Water Maze (MWM) paradigm was used to assess the working memory, then rats were euthanized, the brain excised, three brains were fixed for histological examination (Nissl staining), and the other seven brains were homogenized for AChE activity and Ca2+ concentrations. Data were analyzed statistically, using ANOVA method and P values of ≤0.05 was considered as significant.
Results: In this study, DDVP differentially inhibited AChE activities in various brain regions: cerebellum (86.1%), hippocampus (40.6%), frontal cortex (33.2%), medulla (21.5%), spinal cord (14.8%), and occipital cortex (8.9%). It reduced Ca2+ concentration, but had no effect on the delayed escape latency in the MWM, nor impaired the neuro-architectures. NSO caused increased AChE activities, Ca2+ concentration and reduced escape latency, and improved histologic architectures.
Conclusion: We concluded that NSO reactivated DDVP-induced AChE inhibition and improved memory indices, thus, it may serve as a potential treatment in the management of DDVP poisoning cases
NMDA R/+VDR pharmacological phenotype as a novel therapeutic target in relieving motor–cognitive impairments in Parkinsonism
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
.Aim: 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 functionsin vivo.
Methods: Adult mice were separated into six groups of n¼5 animals each. Body weight
(5 mg/kg) of haloperidol was administered intraperitoneally for 7 days to block dopaminergic
D2receptors 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 recordedin 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.
Result/Discussion: 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 D3intervention 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.
Conclusion: 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
Evaluation of the effects of ascorbic acid on azathioprine-induced alteration in the testes of adult Wistar rats
The use of azathioprine (AZA) in the prevention of organ rejection during transplantation has been
noted in different organs of the body. This study investigates the effect of ascorbic acid on azathioprineinduced alteration in the testes of adult Wistar rats. Thirty male adult Wistar rats were randomly assigned into 5 groups comprising a Control group A and four Treatment groups B to E. Animals in treatment groups B and D received 10 and 20 mg/kg of AZA respectively; whilerats in treatment groups C received 10 mg/kg AZA +25
mg/kg ascorbic acid, and group E received 20 mg/kg of AZA + 50 mg/kg of ascorbic acid. The control group
animals received equal volume of normal saline via orogastric tube, and treatment lasted for 21 days. The testes were excised, weighed and fixed in Bouins’ fluid fortissue histology. Tissue homogenate was used to assay
testosterone level, while blood was also obtained intracardially for glutathione peroxidase studies. Findings revealed significant histological changes in the treatment groups, decreased testosterone levels, and elevated glutathione peroxidase activity in all the treatment groups, compared with control. However, the treatment groups that received ascorbic acid had minimal, butsignificant reduction in the glutathione peroxidase activity compared to treatment groups without ascorbic acid intervention. Use of azathioprine induces significant damage to testicular structure, and this cannot be ameliorated by the use of ascorbic acid
Semaphorin 4B is an ADAM17-cleaved adipokine that inhibits adipocyte differentiation and thermogenesis
Objective: The metalloprotease ADAM17 (also called TACE) plays fundamental roles in homeostasis by shedding key signaling molecules from the cell surface. Although its importance for the immune system and epithelial tissues is well-documented, little is known about the role of ADAM17 in metabolic homeostasis. The purpose of this study was to determine the impact of ADAM17 expression, specifically in adipose tissues, on metabolic homeostasis.Methods: We used histopathology, molecular, proteomic, transcriptomic, in vivo integrative physiological and ex vivo biochemical approaches to determine the impact of adipose tissue-specific deletion of ADAM17 upon adipocyte and whole organism metabolic physiology.Results: ADAM17adipoq-creD/D mice exhibited a hypermetabolic phenotype characterized by elevated energy consumption and increased levels of adipocyte thermogenic gene expression. On a high fat diet, these mice were more thermogenic, while exhibiting elevated expression levels of genes associated with lipid oxidation and lipolysis. This hypermetabolic phenotype protected mutant mice from obesogenic challenge, limiting weight gain, hepatosteatosis and insulin resistance. Activation of beta-adrenoceptors by the neurotransmitter norepinephrine, a key regulator of adipocyte physiology, triggered the shedding of ADAM17 substrates, and regulated ADAM17 expression at the mRNA and protein levels, hence identifying a functional connection between thermogenic licensing and the regulation of ADAM17. Proteomic studies identified Semaphorin 4B (SEMA4B), as a novel ADAM17-shed adipokine, whose expression is regulated by physiological thermogenic cues, that acts to inhibit adipocyte differentiation and dampen thermogenic responses in adipocytes. Transcriptomic data showed that cleaved SEMA4B acts in an autocrine manner in brown adipocytes to repress the expression of genes involved in adipogenesis, thermogenesis, and lipid uptake, storage and catabolism.Conclusions: Our findings identify a novel ADAM17-dependent axis, regulated by beta-adrenoceptors and mediated by the ADAM17-cleaved form of SEMA4B, that modulates energy balance in adipocytes by inhibiting adipocyte differentiation, thermogenesis and lipid catabolism.(c) 2023 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
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
Deletion of iRhom2 protects against diet-inducedobesity by increasing thermogenesis
Objective:Obesity is the result of positive energy balance. It can be caused by excessive energy consumption but also by decreased energydissipation, which occurs under several conditions including when the development or activation of brown adipose tissue (BAT) is impaired. Herewe evaluated whether iRhom2, the essential cofactor for the Tumour Necrosis Factor (TNF) sheddase ADAM17/TACE, plays a role in thepathophysiology of metabolic syndrome.Methods:We challenged WT versus iRhom2 KO mice to positive energy balance by chronic exposure to a high fat diet and then compared theirmetabolic phenotypes. We also carried outex vivoassays with primary and immortalized mouse brown adipocytes to establish the autonomy ofthe effect of loss of iRhom2 on thermogenesis and respiration.Results:Deletion of iRhom2 protected mice from weight gain, dyslipidemia, adipose tissue inflammation, and hepatic steatosis and improvedinsulin sensitivity when challenged by a high fat diet. Crucially, the loss of iRhom2 promotes thermogenesis via BAT activation and beigeadipocyte recruitment, enabling iRhom2 KO mice to dissipate excess energy more efficiently than WT animals. This effect on enhanced ther-mogenesis is cell-autonomous in brown adipocytes as iRhom2 KOs exhibit elevated UCP1 levels and increased mitochondrial proton leak.Conclusion:Our data suggest that iRhom2 is a negative regulator of thermogenesis and plays a role in the control of adipose tissue homeostasisduring metabolic diseaseWellcome Trust strategic award (100574/Z/12/Z) and MRC MDU (MC_UU_12012/