Further Characterization of Intrastriatal Lipopolysaccharide Model of Parkinson’s Disease in C57BL/6 Mice

Parkinson’s disease (PD) is the most common movement disorder, characterized by progressive degeneration of the nigrostriatal pathway, which consists of dopaminergic cell bodies in substantia nigra and their neuronal projections to the striatum. Moreover, PD is associated with an array of non-motor symptoms such as olfactory dysfunction, gastrointestinal dysfunction, impaired regulation of the sleep-wake cycle, anxiety, depression, and cognitive impairment. Inflammation and concomitant oxidative stress are crucial in the pathogenesis of PD. Thus, this study aimed to model PD via intrastriatal injection of the inflammagen lipopolysaccharide (LPS)to investigate if the lesion causes olfactory and motor impairments, inflammation, oxidative stress, and alteration in synaptic proteins in the olfactory bulb, striatum, and colon. Ten µg of LPS was injected unilaterally into the striatum of 27 male C57BL/6 mice, and behavioural assessment was conducted at 4 and 8 weeks post-treatment, followed by tissue collection. Intrastriatal LPS induced motor impairment in C57BL/6 mice at 8 weeks post-treatment evidenced by reduced latency time in the rotarod test. LPS also induced inflammation in the striatum characterized by increased expression of microglial marker Iba-1 and astrocytic marker GFAP, with degeneration of dopaminergic neuronal fibres (reduced tyrosine hydroxylase immunoreactivity), and reduction of synaptic proteins andDJ-1 protein. Additionally, intrastriatal LPS induced inflammation, oxidative stress and alterations in synaptic proteins within the olfactory bulb, although this did not induce a significant impairment in olfactory function. Intrastriatal LPS induced mild inflammatory changes in the distal colon, accompanied by increased protein expression of 3-nitrotyrosine-modified proteins. This model recapitulated the major features of PD such as motor impairment and degeneration of dopaminergic neuronal fibres in the striatum, as well as some pathological changes in the olfactory bulb and colon; thus, this model could be suitable for understanding clinical PD and testing neuroprotective strategies.

Download Full-text

Environmental Enrichment Attenuates Oxidative Stress and Alters Detoxifying Enzymes in an A53T α-Synuclein Transgenic Mouse Model of Parkinson’s Disease

Antioxidants ◽

10.3390/antiox9100928 ◽

2020 ◽

Vol 9 (10) ◽

pp. 928

Author(s):

Jung Hwa Seo ◽

Seong-Woong Kang ◽

Kyungri Kim ◽

Soohyun Wi ◽

Jang Woo Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Olfactory Bulb ◽

Frontal Cortex ◽

Brain Stem ◽

Environmental Enrichment ◽

Brain Regions ◽

Wild Type ◽

Detoxifying Enzymes

Although environmental enrichment (EE) is known to reduce oxidative stress in Parkinson’s disease (PD), the metabolic alternations for detoxifying endogenous and xenobiotic compounds according to various brain regions are not fully elucidated yet. This study aimed to further understand the role of EE on detoxifying enzymes, especially those participating in phase I of metabolism, by investigating the levels of enzymes in various brain regions such as the olfactory bulb, brain stem, frontal cortex, and striatum. Eight-month-old transgenic PD mice with the overexpression of human A53T α-synuclein and wild-type mice were randomly allocated to either standard cage condition or EE for 2 months. At 10 months of age, the expression of detoxifying enzymes was evaluated and compared with wild-type of the same age raised in standard cages. EE improved neurobehavioral outcomes such as olfactory and motor function in PD mice. EE-treated mice showed that oxidative stress was attenuated in the olfactory bulb, brain stem, and frontal cortex. EE also reduced apoptosis and induced cell proliferation in the subventricular zone of PD mice. The overexpression of detoxifying enzymes was observed in the olfactory bulb and brain stem of PD mice, which was ameliorated by EE. These findings were not apparent in the other experimental regions. These results suggest the stage of PD pathogenesis may differ according to brain region, and that EE has a protective effect on the PD pathogenesis by decreasing oxidative stress.

Download Full-text

CNB-001 a Novel Curcumin Derivative, Guards Dopamine Neurons in MPTP Model of Parkinson’s Disease

BioMed Research International ◽

10.1155/2014/236182 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 25

Author(s):

Richard L. Jayaraj ◽

Namasivayam Elangovan ◽

Krishnan Manigandan ◽

Sonu Singh ◽

Shubha Shukla

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Therapeutic Potential ◽

Motor Impairment ◽

Dopamine Neurons ◽

Ultrastructural Changes ◽

Monoamine Transporter ◽

Postmortem Studies ◽

Mptp Model

Copious experimental and postmortem studies have shown that oxidative stress mediated degeneration of nigrostriatal dopaminergic neurons underlies Parkinson’s disease (PD) pathology. CNB-001, a novel pyrazole derivative of curcumin, has recently been reported to possess various neuroprotective properties. This study was designed to investigate the neuroprotective mechanism of CNB-001 in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent model of PD. Administration of MPTP (30 mg/kg for four consecutive days) exacerbated oxidative stress and motor impairment and reduced tyrosine hydroxylase (TH), dopamine transporter, and vesicular monoamine transporter 2 (VMAT2) expressions. Moreover, MPTP induced ultrastructural changes such as distorted cristae and mitochondrial enlargement in substantia nigra and striatum region. Pretreatment with CNB-001 (24 mg/kg) not only ameliorated behavioral anomalies but also synergistically enhanced monoamine transporter expressions and cosseted mitochondria by virtue of its antioxidant action. These findings support the neuroprotective property of CNB-001 which may have strong therapeutic potential for treatment of PD.

Download Full-text

Autonomic Function in Patients With Parkinson’s Disease: From Rest to Exercise

Frontiers in Physiology ◽

10.3389/fphys.2021.626640 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jeann L. Sabino-Carvalho ◽

James P. Fisher ◽

Lauro C. Vianna

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Motor Impairment ◽

Exercise Intolerance ◽

Motor Nucleus ◽

Motor Impairments ◽

Dorsal Motor Nucleus ◽

Clinically Significant ◽

Underlying Mechanisms

Parkinson’s disease (PD) is a common neurodegenerative disorder classically characterized by symptoms of motor impairment (e.g., tremor and rigidity), but also presenting with important non-motor impairments. There is evidence for the reduced activity of both the parasympathetic and sympathetic limbs of the autonomic nervous system at rest in PD. Moreover, inappropriate autonomic adjustments accompany exercise, which can lead to inadequate hemodynamic responses, the failure to match the metabolic demands of working skeletal muscle and exercise intolerance. The underlying mechanisms remain unclear, but relevant alterations in several discrete central regions (e.g., dorsal motor nucleus of the vagus nerve, intermediolateral cell column) have been identified. Herein, we critically evaluate the clinically significant and complex associations between the autonomic dysfunction, fatigue and exercise capacity in PD.

Download Full-text

Depression in Parkinson’s Disease: The Contribution from Animal Studies

Parkinson s Disease ◽

10.1155/2017/9124160 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Jéssica Lopes Fontoura ◽

Camila Baptista ◽

Flávia de Brito Pedroso ◽

José Augusto Pochapski ◽

Edmar Miyoshi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Animal Studies ◽

Life Quality ◽

Significant Loss ◽

Nigrostriatal Pathway ◽

Depression And Anxiety ◽

Motor Impairments ◽

Loss Of Life ◽

Effective Drugs

Besides being better known for causing motor impairments, Parkinson’s disease (PD) can also cause many nonmotor symptoms, like depression and anxiety, which can cause significant loss of life quality and may not respond to regular drugs treatment. In this review, we discuss the depression in PD, based on data from studies in humans and rodents. Depression frequency seems higher in PD patients than in general population, despite high variation in data due to diagnosis disparities. Development of depression in PD seems more likely to be caused by the nigrostriatal pathway degeneration than as a consequence of the awareness of disease prognostic, and it seems to be related to dopaminergic, noradrenergic, and serotoninergic synapses deficits. The dopaminergic role could be more significant, since it can modulate the release of the others, and its depletion is progressive, due to the degenerative feature of PD. Highly regarded in major depression, serotonin can be depleted in rats after nigrostriatal damage, but data from human patients are more conflicting. Animal studies can help in understanding the neurobiological mechanisms of depression in PD and the pursuit for more effective drugs for its treatment, but they lack the complexity of the disease progression, especially the nondopaminergic degeneration.

Download Full-text

Neuroprotective and Anti-Inflammatory Effects of Evernic Acid in an MPTP-Induced Parkinson’s Disease Model

International Journal of Molecular Sciences ◽

10.3390/ijms22042098 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2098

Author(s):

Seulah Lee ◽

Yeon Ji Suh ◽

Seonguk Yang ◽

Dong Geun Hong ◽

Akihito Ishigami ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Neuronal Loss ◽

Motor Dysfunction ◽

Nigrostriatal Pathway ◽

Neuroprotective Effects ◽

Anti Inflammatory

Oxidative stress, mitochondrial dysfunction, and neuroinflammation are strongly associated with the pathogenesis of Parkinson’s disease (PD), which suggests that anti-oxidative and anti-inflammatory compounds might provide an alternative treatment for PD. Here, we evaluated the neuroprotective effects of evernic aid (EA), which was screened from a lichen library provided by the Korean Lichen Research Institute at Sunchon National University. EA is a secondary metabolite generated by lichens, including Ramalina, Evernia, and Hypogymnia, and several studies have described its anticancer, antifungal, and antimicrobial effects. However, the neuroprotective effects of EA have not been studied. We found that EA protected primary cultured neurons against 1-methyl-4-phenylpyridium (MPP+)-induced cell death, mitochondrial dysfunction, and oxidative stress, and effectively reduced MPP+-induced astroglial activation by inhibiting the NF-κB pathway. In vivo, EA ameliorated MPTP-induced motor dysfunction, dopaminergic neuronal loss, and neuroinflammation in the nigrostriatal pathway in C57BL/6 mice. Taken together, our findings demonstrate that EA has neuroprotective and anti-inflammatory effects in PD models and suggest that EA is a potential therapeutic candidate for PD.

Download Full-text

Increased Activity of Tyrosine Hydroxylase Leads to Elevated Amphetamine Response and Markers of Oxidative Stress in Transgenic Mice

10.1101/188318 ◽

2017 ◽

Cited By ~ 1

Author(s):

Laura M. Vecchio ◽

M. Kristel Bermejo ◽

Amy Dunn ◽

Marija Milenkovic ◽

Nikhil Urs ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Tyrosine Hydroxylase ◽

Dopamine Synthesis ◽

Dopamine Turnover ◽

Nigrostriatal Pathway ◽

Adult Mice

AbstractIn Parkinson’s disease, noradrenergic cells of the locus coeruleus and dopamine cells within the nigrostriatal pathway undergo profound degeneration. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the production of all catecholamines, including dopamine and noradrenaline, and is selectively expressed in the cells that produce these neurotransmitters. In vitro studies have previously shown that the TH-synthetic system can contribute to the formation of reactive oxygen species. In addition, animal models of dopamine mishandling demonstrated that free dopamine is neurotoxic. To examine how increased TH activity might influence catecholamine systems in vivo, we generated TH-overexpressing mice (TH-HI) with six total copies of the TH murine gene. A commensurate increase in TH mRNA produced a threefold increase in both total TH protein and phosphorylated TH levels. We found an increased rate of dopamine synthesis in both young and adult mice, reflected by the accumulation of L-DOPA following NSD-1015 administration, as well as elevated dopamine tissue content in young mice and an increased presence of dopamine metabolites at both ages. Adult mice show no difference in baseline locomotor behaviour compared to wildtype littermates, but a have potentiated response to amphetamine. In addition to elevated dopamine turnover in the striatum, TH-HI mice show reduced levels of glutathione and increased levels of cysteinylated catechols. These results indicate that a heightened level of active TH can produce oxidative stress, and may represent a source of toxicity that is specific to catecholamine cells, which are most vulnerable to degeneration in Parkinson’s disease.

Download Full-text

Hydroxychloroquine Attenuated Motor Impairment and Oxidative Stress in a Rat 6-hydroxydopamine Model of Parkinson's Disease

10.21203/rs.3.rs-890394/v1 ◽

2021 ◽

Author(s):

Seyed Zanyar Athari ◽

Fereshteh Farajdokht ◽

Saeed Sadigh Eteghad ◽

Daryoush Mohajeri ◽

Mir Alireza Nourazar ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Motor Impairment ◽

Muscle Rigidity ◽

Behavioral Tests ◽

Protein Levels ◽

6 Hydroxydopamine ◽

Gpx Activity

Abstract Background: Parkinson's disease (PD) is associated with the destruction of dopaminergic neurons in the substantia nigra (SN). Hydroxychloroquine (HCQ) has the capability to cross the blood-brain barrier and promote a neuroprotective potential. This study evaluated the effects of HCQ on the 6-hydroxydopamine (6-OHDA)-induced PD model in rats.Methods: Wistar rats were randomly divided into sham, PD, PD+levodopa, and PD+HCQ groups. The PD model was induced by a stereotactic administration of 6-OHDA into the left SN pars compacta (SNpc) and confirmed by rotation and the Murprogo’s tests. HCQ (100 mg/kg, p.o.) and levodopa (12 mg/kg, p.o.) were administered once a day for 21 days. Three weeks after surgery, the behavioral tests were performed. Brain lipid peroxidation index (MDA), glutathione peroxidase activity (GPx), total antioxidant capacity (TAC) levels, and α-synuclein protein expression in the SN were also measured. Results: The behavioral tests demonstrated that induction of PD increased the muscle rigidity and the number of rotations, which were reversed by HCQ treatment. Also, induction of PD was associated with an increase in α-synuclein protein levels and MDA and decreased TAC levels and GPx activity. However, HCQ decreased α-synuclein and MDA levels while increased TAC levels and GPx activity. Additionally, histopathological data showed that HCQ protects dopaminergic neurons against 6-OHDA-induced toxicity.Conclusion: According to the results, HCQ has a beneficial effect in improving PD-related pathophysiology, in part, by mitigating oxidative stress and protecting the dopaminergic neurons in the SN.

Download Full-text

Efficacy of Hypericum perforatum extract on ultrastructural changes in brain and oxidative damage in Parkinson’s disease

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11ispl4.4556 ◽

2020 ◽

Vol 11 (SPL4) ◽

pp. 2793-2798

Author(s):

Chandran Satheesh Kumar ◽

Srinivasagam Raja Sankar ◽

Kaliyaperumal Prabu

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Parkinson Disease ◽

Hypericum Perforatum ◽

Disease Model ◽

Post Treatment ◽

Ultrastructural Changes ◽

Pre Treatment ◽

The Brain

Parkinson’s disease (PD) is a serious chronic and progressive neurological disorder. Hypericum perforatum (H. perforatum) is a plant generally used as an antidepressant and therapy for many neurodegenerative disorders. The present study evaluates the action of Hypericum perforatum extract on MPTP induced oxidative stress and ultrastructural changes in the Parkinson disease model. For this research study, Parkinson disease in mice were induced using MPTP and Hypericum perforatum methanolic extract were given in the pre-treatment and post-treatment condition. After the treatment, the oxidative stress was measured using TBARS levels and the activities of GSH, GPx, CAT and SOD in brain tissues. The ultrastructural changes in brain mitochondria caused by MPTP toxicity was studied after Hypericum perforatum extract therapy using TEM images. The present study showed that HPE extract is able to balance the oxidative stress and antioxidants in the brain tissue of MPTP administered rats. The damaged nuclei in the brain recovered to the normal condition due to this extract therapy. Finally, to conclude, Hypericum perforatum extract post-treatment offers potential brain protection against MPTP-induced Parkinson’s disease than pre-treatment.

Download Full-text