Cannabinoid Receptor Modulation in the 3-Acetylpyridine Cerebellar Ataxia Mouse Model

2022 ◽  
Author(s):  
Hoda Ranjbar ◽  
Monavareh Soti ◽  
mahyar janahmadi ◽  
Kristi A. Kohlmeier ◽  
vahid sheibani ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Mouse Model ◽  
Cerebellar Ataxia ◽  
Cannabinoid Receptors ◽  
Motor Coordination ◽  
Neurodegenerative Disorder ◽  
Therapeutic Drug ◽  
Cannabinoid Type 1 Receptor ◽  
Receptor Modulation ◽  
Abnormal Gait

Abstract Cerebellar ataxia is a neurodegenerative disorder leading to severe motor incoordination. Recently it has been suggested that cannabinoids play a role in modulation of ataxic symptoms. In order to understand the possible therapeutic effect of cannabinoids for management of cerebellar ataxia, we used cannabinoid agonist/antagonists to target the cannabinoid type 1 receptor (CB1R) in the 3 acetyl pyridine (3AP) mouse model of ataxia. The role of the CB1R was examined by using three different doses of the CB1R agonist, WIN55,212-2 (WIN; 0.1, 0.5, 1 mg/kg) administrated 30 min prior to 3AP (55 mg/kg, i.p.) which leads to motor impairment through destruction of the inferior olive. In some recordings, the CB1R antagonist AM251(1 mg/kg) was given in combination with WIN. Locomotor activity and motor coordination were impaired by 3AP, and the application of WIN did not ameliorate this effect. However, the abnormal gait, rearing and grooming caused by 3AP were prevented by co-administration of AM251 with WIN. While the addition of the CB1R antagonist inhibition improved some ataxic symptoms, there was no effect of AM251 on balance or locomotor activity when co-administrated with WIN. Behavioral testing indicated that not only did WIN fail to exert any protective effect on ataxic symptoms, it exacerbated ataxic symptoms, suggesting that CB1R agonists may not be the ideal therapeutic drug in this disorder. When taken together, the findings from the present study indicate that cannabinoid modulation of ataxia symptoms may not act solely through CB1Rs and other cannabinoid receptors should be consider in future studies.

scholarly journals Abnormal gait, reduced locomotor activity and impaired motor coordination in Dgcr2 -deficient mice

2016 ◽  
Vol 5 ◽  
pp. 120-126 ◽  
Author(s):  
Shin-ichiro Mugikura ◽  
Akira Katoh ◽  
Satoshi Watanabe ◽  
Minoru Kimura ◽  
Kagemasa Kajiwara
Keyword(s):  
Locomotor Activity ◽  
Motor Coordination ◽  
Abnormal Gait ◽  
Deficient Mice

scholarly journals Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

2021 ◽  
Vol 12 ◽  
Author(s):  
Yaqiong Ren ◽  
Yuqi Shen ◽  
Nuo Si ◽  
Shiqi Fan ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Spatial Learning ◽  
Motor Coordination ◽  
Neurodegenerative Disorder ◽  
Clinical Manifestations ◽  
Sensorimotor Gating ◽  
Skeletal Malformation ◽  
Brain Calcification ◽  
Deficient Mice ◽  
Spatial Learning Memory

BackgroundPrimary familial brain calcification (PFBC, OMIM#213600), also known as Fahr’s disease, is a rare autosomal dominant or recessive neurodegenerative disorder characterized by bilateral and symmetrical microvascular calcifications affecting multiple brain regions, particularly the basal ganglia (globus pallidus, caudate nucleus, and putamen) and thalamus. The most common clinical manifestations include cognitive impairment, neuropsychiatric signs, and movement disorders. Loss-of-function mutations in SLC20A2 are the major genetic causes of PFBC.ObjectiveThis study aimed to investigate whether Slc20a2 knockout mice could recapitulate the dynamic processes and patterns of brain calcification and neurological symptoms in patients with PFBC. We comprehensively evaluated brain calcifications and PFBC-related behavioral abnormalities in Slc20a2-deficient mice.MethodsBrain calcifications were analyzed using classic calcium-phosphate staining methods. The Morris water maze, Y-maze, and fear conditioning paradigms were used to evaluate long-term spatial learning memory, working memory, and episodic memory, respectively. Sensorimotor gating was mainly assessed using the prepulse inhibition of the startle reflex program. Spontaneous locomotor activity and motor coordination abilities were evaluated using the spontaneous activity chamber, cylinder test, accelerating rotor-rod, and narrowing balance beam tests.ResultsSlc20a2 homozygous knockout (Slc20a2-HO) mice showed congenital and global developmental delay, lean body mass, skeletal malformation, and a high proportion of unilateral or bilateral eye defects. Brain calcifications were detected in the hypothalamus, ventral thalamus, and midbrain early at postnatal day 80 in Slc20a2-HO mice, but were seldom found in Slc20a2 heterozygous knockout (Slc20a2-HE) mice, even at extremely old age. Slc20a2-HO mice exhibited spatial learning memory impairments and sensorimotor gating deficits while exhibiting normal working and episodic memories. The general locomotor activity, motor balance, and coordination abilities were not statistically different between Slc20a2-HO and wild-type mice after adjusting for body weight, which was a major confounding factor in our motor function evaluations.ConclusionThe human PFBC-related phenotypes were highly similar to those in Slc20a2-HO mice. Therefore, Slc20a2-HO mice might be suitable for the future evaluation of neuropharmacological intervention strategies targeting cognitive and neuropsychiatric impairments.

scholarly journals Lack of riluzole efficacy in the progression of the neurodegenerative phenotype in a new conditional mouse model of striatal degeneration

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3240
Author(s):  
Grzegorz Kreiner ◽  
Katarzyna Rafa-Zabłocka ◽  
Piotr Chmielarz ◽  
Monika Bagińska ◽  
Irena Nalepa
Keyword(s):  
Mouse Model ◽  
Motor Coordination ◽  
Neurodegenerative Disorder ◽  
Proliferating Cells ◽  
High Expectations ◽  
Neuronal Markers ◽  
Genetic Ablation ◽  
Progressive Degeneration ◽  
Positive Modulator ◽  
Treatment Paradigm

BackgroundHuntington’s disease (HD) is a rare familial autosomal dominant neurodegenerative disorder characterized by progressive degeneration of medium spiny neurons (MSNs) located in the striatum. Currently available treatments of HD are only limited to alleviating symptoms; therefore, high expectations for an effective therapy are associated with potential replacement of lost neurons through stimulation of postnatal neurogenesis. One of the drugs of potential interest for the treatment of HD is riluzole, which may act as a positive modulator of adult neurogenesis, promoting replacement of damaged MSNs. The aim of this study was to evaluate the effects of chronic riluzole treatment on a novel HD-like transgenic mouse model, based on the genetic ablation of the transcription factor TIF-IA. This model is characterized by selective and progressive degeneration of MSNs.MethodsSelective ablation of TIF-IA in MSNs (TIF-IAD1RCremice) was achieved by Cre-based recombination driven by the dopamine 1 receptor (D1R) promoter in the C57Bl/6N mouse strain. Riluzole was administered for 14 consecutive days (5 mg/kg, i.p.; 1× daily) starting at six weeks of age. Behavioral analysis included a motor coordination test performed on 13-week-old animals on an accelerated rotarod (4–40 r.p.m.; 5 min). To visualize the potential effects of riluzole treatment, the striata of the animals were stained by immunohistochemistry (IHC) and/or immunofluorescence (IF) with Ki67 (marker of proliferating cells), neuronal markers (NeuN, MAP2, DCX), and markers associated with neurodegeneration (GFAP, 8OHdG, FluoroJade C). Additionally, the morphology of dendritic spines of neurons was assessed by a commercially available FD Rapid Golgi Stain™ Kit.ResultsA comparative analysis of IHC staining patterns with chosen markers for the neurodegeneration process in MSNs did not show an effect of riluzole on delaying the progression of MSN cell death despite an observed enhancement of cell proliferation as visualized by the Ki67 marker. A lack of a riluzole effect was also reflected by the behavioral phenotype associated with MSN degeneration. Moreover, the analysis of dendritic spine morphology did not show differences between mutant and control animals.DiscussionDespite the observed increase in newborn cells in the subventricular zone (SVZ) after riluzole administration, our study did not show any differences between riluzole-treated and non-treated mutants, revealing a similar extent of the neurodegenerative phenotype evaluated in 13-week-old TIF-IAD1RCreanimals. This could be due to either the treatment paradigm (relatively low dose of riluzole used for this study) or the possibility that the effects were simply too weak to have any functional meaning. Nevertheless, this study is in line with others that question the effectiveness of riluzole in animal models and raise concerns about the utility of this drug due to its rather modest clinical efficacy.

Physical exercise protects dynamic balance and motor coordination of rats treated with vincristine

2020 ◽  
Vol 19 (5) ◽  
pp. 336
Author(s):  
Luiza Minato Sagrillo ◽  
Viviane Nogueira De Zorzi ◽  
Luiz Fernando Freire Royes ◽  
Michele Rechia Fighera ◽  
Beatriz Da Silva Rosa Bonadiman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Locomotor Activity ◽  
Physical Exercise ◽  
Motor Coordination ◽  
Dynamic Balance ◽  
Exercise Group ◽  
Adult Rats ◽  
The Central Nervous System ◽  
Stress Damage ◽  
Training Protocol

Physical exercise has been shown to be an important modulator of the antioxidant system and neuroprotective in several diseases and treatments that affect the central nervous system. In this sense, the present study aimed to evaluate the effect of physical exercise in dynamic balance, motor coordination, exploratory locomotor activity and in the oxidative and immunological balance of rats treated with vincristine (VCR). For that, 40 adult rats were divided into two groups: exercise group (6 weeks of swimming, 1h/day, 5 days/week, with overload of 5% of body weight) and sedentary group. After training, rats were treated with 0.5 mg/kg of vincristine sulfate for two weeks or with the same dose of 0.9% NaCl. The behavioral tests were conducted 1 and 7 days after each dose of VCR. On day 15 we carried out the biochemical analyzes of the cerebellum. The physical exercise was able to protect against the loss of dynamic balance and motor coordination and, had effect per se in the exploratory locomotor activity, and neutralize oxidative stress, damage DNA and immune damage caused by VCR up to 15 days after the end of the training protocol. In conclusion, we observed that previous physical training protects of the damage motor induced by vincristine.Key-words: exercise, oxidative stress, neuroprotection, cerebellum.

scholarly journals Intermittent Hypoxic Conditioning Rescues Cognition and Mitochondrial Bioenergetic Profile in the Triple Transgenic Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 22 (1) ◽  
pp. 461
Author(s):  
Sónia C. Correia ◽  
Nuno J. Machado ◽  
Marco G. Alves ◽  
Pedro F. Oliveira ◽  
Paula I. Moreira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Brain Cortex ◽  
Neurodegenerative Disorder ◽  
Special Focus ◽  
Mitochondrial Bioenergetics ◽  
Related Phenotype ◽  
Brain Resilience ◽  
The Brain

The lack of effective disease-modifying therapeutics to tackle Alzheimer’s disease (AD) is unsettling considering the actual prevalence of this devastating neurodegenerative disorder worldwide. Intermittent hypoxic conditioning (IHC) is a powerful non-pharmacological procedure known to enhance brain resilience. In this context, the aim of the present study was to investigate the potential long-term protective impact of IHC against AD-related phenotype, putting a special focus on cognition and mitochondrial bioenergetics and dynamics. For this purpose, six-month-old male triple transgenic AD mice (3×Tg-AD) were submitted to an IHC protocol for two weeks and the behavioral assessment was performed at 8.5 months of age, while the sacrifice of mice occurred at nine months of age and their brains were removed for the remaining analyses. Interestingly, IHC was able to prevent anxiety-like behavior and memory and learning deficits and significantly reduced brain cortical levels of amyloid-β (Aβ) in 3×Tg-AD mice. Concerning brain energy metabolism, IHC caused a significant increase in brain cortical levels of glucose and a robust improvement of the mitochondrial bioenergetic profile in 3×Tg-AD mice, as mirrored by the significant increase in mitochondrial membrane potential (ΔΨm) and respiratory control ratio (RCR). Notably, the improvement of mitochondrial bioenergetics seems to result from an adaptative coordination of the distinct but intertwined aspects of the mitochondrial quality control axis. Particularly, our results indicate that IHC favors mitochondrial fusion and promotes mitochondrial biogenesis and transport and mitophagy in the brain cortex of 3×Tg-AD mice. Lastly, IHC also induced a marked reduction in synaptosomal-associated protein 25 kDa (SNAP-25) levels and a significant increase in both glutamate and GABA levels in the brain cortex of 3×Tg-AD mice, suggesting a remodeling of the synaptic microenvironment. Overall, these results demonstrate the effectiveness of the IHC paradigm in forestalling the AD-related phenotype in the 3×Tg-AD mouse model, offering new insights to AD therapy and forcing a rethink concerning the potential value of non-pharmacological interventions in clinical practice.

scholarly journals Serotonin 6 receptor modulation reduces locomotor activity in C57BL/6J mice

2021 ◽  
Vol 1757 ◽  
pp. 147313
Author(s):  
Brandon L. Oliver ◽  
Alma E. Pahua ◽  
Kristianna Hitchcock ◽  
Dionisio A. Amodeo
Keyword(s):  
Locomotor Activity ◽  
Receptor Modulation

Neuroprotective Effects of a GLP-2 Analogue in the MPTP Parkinson’s Disease Mouse Model

2021 ◽  
pp. 1-15
Author(s):  
Zijuan Zhang ◽  
Li Hao ◽  
Ming Shi ◽  
Ziyang Yu ◽  
Simai Shao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Mouse Model ◽  
Neurodegenerative Disorder ◽  
Enzyme Linked Immunosorbent Assay ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Expression Levels ◽  
Dual Agonist

Background: Glucagon-like peptide 2 (GLP-2) is a peptide hormone derived from the proglucagon gene expressed in the intestines, pancreas and brain. Some previous studies showed that GLP-2 improved aging and Alzheimer’s disease related memory impairments. Parkinson’s disease (PD) is a progressive neurodegenerative disorder, and to date, there is no particular medicine reversed PD symptoms effectively. Objective: The aim of this study was to evaluate neuroprotective effects of a GLP-2 analogue in the 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) PD mouse model. Methods: In the present study, the protease resistant Gly(2)-GLP-2 (50 nmol/kg ip.) analogue has been tested for 14 days by behavioral assessment, transmission electron microscope, immunofluorescence histochemistry, enzyme-linked immunosorbent assay and western blot in an acute PD mouse model induced by MPTP. For comparison, the incretin receptor dual agonist DA5-CH was tested in a separate group. Results: The GLP-2 analogue treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement imbalance of mice. Gly(2)-GLP-2 treatment also protected dopaminergic neurons and restored tyrosine hydroxylase expression levels in the substantia nigra. Gly(2)-GLP-2 furthermore reduced the inflammation response as seen in lower microglia activation, and decreased NLRP3 and interleukin-1β pro-inflammatory cytokine expression levels. In addition, the GLP-2 analogue improved MPTP-induced mitochondrial dysfunction in the substantia nigra. The protective effects were comparable to those of the dual agonist DA5-CH. Conclusion: The present results demonstrate that Gly(2)-GLP-2 can attenuate NLRP3 inflammasome-mediated inflammation and mitochondrial damage in the substantia nigra induced by MPTP, and Gly(2)-GLP-2 shows neuroprotective effects in this PD animal model.

scholarly journals Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus

2015 ◽  
Vol 99 ◽  
pp. 600-609 ◽  
Author(s):  
Jenny Morgenweck ◽  
Kevin J. Frankowski ◽  
Thomas E. Prisinzano ◽  
Jeffrey Aubé ◽  
Laura M. Bohn
Keyword(s):  
Mouse Model ◽  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Receptor Modulation

scholarly journals Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 22 (22) ◽  
pp. 12256
Author(s):  
Estibaliz González de San Román ◽  
Alberto Llorente-Ovejero ◽  
Jonatan Martínez-Gardeazabal ◽  
Marta Moreno-Rodríguez ◽  
Lydia Giménez-Llort ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fatty Acid ◽  
Motor Cortex ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Neurodegenerative Disorder ◽  
Transgenic Mouse Model ◽  
Lipid Species ◽  
Triple Transgenic Mouse

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in aging populations. Recently, the regulation of neurolipid-mediated signaling and cerebral lipid species was shown in AD patients. The triple transgenic mouse model (3xTg-AD), harboring βAPPSwe, PS1M146V, and tauP301L transgenes, mimics many critical aspects of AD neuropathology and progressively develops neuropathological markers. Thus, in the present study, 3xTg-AD mice have been used to test the involvement of the neurolipid-based signaling by endocannabinoids (eCB), lysophosphatidic acid (LPA), and sphingosine 1-phosphate (S1P) in relation to the lipid deregulation. [35S]GTPγS autoradiography was used in the presence of specific agonists WIN55,212-2, LPA and CYM5442, to measure the activity mediated by CB1, LPA1, and S1P1 Gi/0 coupled receptors, respectively. Consecutive slides were used to analyze the relative intensities of multiple lipid species by MALDI Mass spectrometry imaging (MSI) with microscopic anatomical resolution. The quantitative analysis of the astrocyte population was performed by immunohistochemistry. CB1 receptor activity was decreased in the amygdala and motor cortex of 3xTg-AD mice, but LPA1 activity was increased in the corpus callosum, motor cortex, hippocampal CA1 area, and striatum. Conversely, S1P1 activity was reduced in hippocampal areas. Moreover, the observed modifications on PC, PA, SM, and PI intensities in different brain areas depend on their fatty acid composition, including decrease of polyunsaturated fatty acid (PUFA) phospholipids and increase of species containing saturated fatty acids (SFA). The regulation of some lipid species in specific brain regions together with the modulation of the eCB, LPA, and S1P signaling in 3xTg-AD mice indicate a neuroprotective adaptation to improve neurotransmission, relieve the myelination dysfunction, and to attenuate astrocyte-mediated neuroinflammation. These results could contribute to identify new therapeutic strategies based on the regulation of the lipid signaling in familial AD patients.

scholarly journals An Atypical Case of Catatonia, Abnormal Gait and Psychosis in an Adolescent with Chronic Cannabis Use

2021 ◽  
pp. 1-3
Author(s):  
Pooja Palkar ◽  
◽  
Sagarika Ray ◽  
Keyword(s):  
Cannabinoid Receptors ◽  
Oral Intake ◽  
Brain Regions ◽  
Cannabis Use ◽  
Unique Case ◽  
Open Chain ◽  
Walking Gait ◽  
The Past ◽  
Abnormal Gait ◽  
History Of

An association between cannabis and psychosis is well established. Cannabis use is known to precipitate schizophrenia in vulnerable individuals and it can exacerbate existing psychosis. However, there is a paucity of knowledge about the emergence of catatonia and abnormal gait associated with cannabis use. History of cannabis use is associated with long-lasting changes in open-chain elements of walking gait. Cannabinoid receptors are located in movement-related brain regions and cannabis use is suggested to affect gait. This report is a unique case of a 16-year-old male with no known past medical history, no past psychiatric history, with family history significant for psychosis who presented to the hospital for bizarre, disorganized behavior, and decreased oral intake following heavy cannabis use over the past three months in the context of a break-up. Upon arrival, he was found to be in a catatonic state with an impaired gait. As catatonia resolved with treatment, he was able to speak and the psychosis surfaced which was addressed with antipsychotics. This case report highlights an atypical but serious clinical picture observed to be precipitated by chronic, heavy cannabis use.

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