Electroacupuncture therapy ameliorates motor dysfunction via brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in a mouse model of Parkinson's disease

2019 ◽  
Author(s):  
Malk Eun Pak ◽  
Sung Min Ahn ◽  
Da Hee Jung ◽  
Hong Ju Lee ◽  
Ki Tae Ha ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Mouse Model ◽  
Mouse Models ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Dopaminergic Neuron ◽  
Motor Dysfunction ◽  
Protective Effects ◽  
Neuron Loss ◽  
Dopaminergic Neuron Loss

Abstract Parkinson’s disease (PD) is characterized by dopaminergic neuron loss in the substantia nigra. However, specific sensory stimulation via electroacupuncture (EA) therapy may attenuate this loss by promoting the expression of endogenous neurotrophic factors in a manner similar to physical therapy. We investigated the potential protective effects of EA on dopaminergic neurons in a mouse model of PD and whether these effects are associated with the promotion of endogenous brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Mouse models of PD were generated using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine. Motor performance was assessed using behavioral tests, and Western blot experiments, enzyme-linked immunosorbent assays, and immunohistochemical assays were performed. In both mouse models, EA treatment ameliorated motor impairments and dopaminergic neuron loss; these changes were accompanied by increases in BDNF and GDNF. In the MPTP group, EA treatment improved motor dysfunction by attenuating dopaminergic neuron loss in the substantia nigra, similar to the effects of levodopa. EA treatment significantly upregulated BDNF and GDNF expression in both the substantia nigra and striatum. Moreover, EA treatment induced the expression of cAMP response element binding protein (CREB) as well as Akt and Pitx3 in dopaminergic neurons in the substantia nigra. However, levodopa treatment did not induce BDNF/GDNF activation or related signaling factors. Thus, EA therapy may exert protective effects on dopaminergic neurons by upregulating the expression of BDNF, GDNF, and related signaling factors, thereby improving motor function. Hence, EA may represent an effective adjuvant therapy for motor deficits in patients with PD.

scholarly journals Rapid Induction of Dopaminergic Neuron Loss Accompanied by Lewy Body-Like Inclusions in A53T BAC-SNCA Transgenic Mice

2021 ◽  
Author(s):  
Shinya Okuda ◽  
Norihito Uemura ◽  
Masanori Sawamura ◽  
Tomoyuki Taguchi ◽  
Masashi Ikuno ◽  
...  
Keyword(s):  
Dopaminergic Neuron ◽  
Motor Dysfunction ◽  
Substantia Nigra Pars Compacta ◽  
Positive Density ◽  
Post Injection ◽  
Wild Type ◽  
Comparable Amount ◽  
Neuron Loss ◽  
Short Period ◽  
Dopaminergic Neuron Loss

Abstract BackgroundParkinson’s disease (PD) is the most common neurodegenerative movement disorder. Pathological features of PD include dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and intraneuronal α-Synuclein (α-Syn) inclusions called Lewy bodies (LBs). Since there is no treatment to either halt or slow the progression of PD, it is highly demanded to establish a rodent model that recapitulates the clinicopathological features of PD within a short period to efficiently investigate the pathological mechanisms and test disease-modifying therapies (DMTs).MethodsWe injected human and mouse α-Syn-preformed fibrils (hPFFs and mPFFs, respectively) into the hemilateral dorsal striatum of wild-type mice, wild-type human α-Syn bacterial artificial chromosome (BAC) transgenic (WT BAC-SNCA Tg) mice, and A53T human α-Syn BAC transgenic (A53T BAC-SNCA Tg) mice, and conducted pathological and behavioral analyses.ResultsWT BAC-SNCA Tg and A53T BAC-SNCA Tg mice expressed a comparable amount of α-Syn (2.9 and 2.7-fold more α-Syn, respectively, than wild-type mice) in the brains. mPFF injections induced more severe α-Syn pathology in most brain regions, including the ipsilateral SNpc, than hPFF injections in all genotypes at 1 month post-injection. Among the mPFF-injected mice, the A53T BAC-SNCA Tg mice exhibited the most severe α-Syn pathology as early as 0.5 month (2 weeks) post-injection. Consistent with these observations, in vitro fibrillization assay revealed that a mixture of A53T human α-Syn and mouse α-Syn seeded with mPFFs aggregated most rapidly among the conditions tested. The mPFF-injected A53T BAC-SNCA Tg mice showed a 38% reduction in tyrosine hydroxylase (TH)-positive neurons in the ipsilateral SNpc, apomorphine-induced rotational behavior, and motor dysfunction at 2 months post-injection. Notably, the reduction in TH-positive density in the striatum and microglial activation preceded the obvious TH-positive neuron loss in the SNpc.ConclusionsOur data indicate that the extent of α-Syn pathology induced by α-Syn PFF injection depends on the types of α-Syn PFFs and exogenously expressed α-Syn in Tg mice. The mPFF-injected A53T BAC-SNCA Tg mice recapitulate the pathological processes of PD more rapidly than previously reported mouse models, suggesting their usefulness for testing DMTs as well as analyzing the pathological mechanisms.

Effects of age-related dopaminergic neuron loss in the substantia nigra on the circadian rhythms of locomotor activity in mice

2012 ◽  
Vol 74 (3-4) ◽  
pp. 210-215 ◽  
Author(s):  
Makoto Tanaka ◽  
Eriko Yamaguchi ◽  
Mami Takahashi ◽  
Kana Hashimura ◽  
Takao Shibata ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Circadian Rhythms ◽  
Substantia Nigra ◽  
Dopaminergic Neuron ◽  
Neuron Loss ◽  
Age Related ◽  
Dopaminergic Neuron Loss

scholarly journals Noscapine Prevents Rotenone-Induced Neurotoxicity: Involvement of Oxidative Stress, Neuroinflammation and Autophagy Pathways

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4627
Author(s):  
Richard Jayaraj ◽  
Rami Beiram ◽  
Sheikh Azimullah ◽  
Nagoor M. F. ◽  
Shreesh Ojha ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Enzymes ◽  
Substantia Nigra ◽  
Rat Model ◽  
Dopaminergic Neurons ◽  
Dopaminergic Neuron ◽  
Substantia Nigra Pars Compacta ◽  
Inflammatory Factors ◽  
Lysosomal Degradation ◽  
Dopaminergic Neuron Loss

Parkinson’s disease is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) and the resultant loss of dopamine in the striatum. Various studies have shown that oxidative stress and neuroinflammation plays a major role in PD progression. In addition, the autophagy lysosome pathway (ALP) plays an important role in the degradation of aggregated proteins, abnormal cytoplasmic organelles and proteins for intracellular homeostasis. Dysfunction of ALP results in the accumulation of α-synuclein and the loss of dopaminergic neurons in PD. Thus, modulating ALP is becoming an appealing therapeutic intervention. In our current study, we wanted to evaluate the neuroprotective potency of noscapine in a rotenone-induced PD rat model. Rats were administered rotenone injections (2.5 mg/kg, i.p.,) daily followed by noscapine (10 mg/kg, i.p.,) for four weeks. Noscapine, an iso-qinulinin alkaloid found naturally in the Papaveraceae family, has traditionally been used in the treatment of cancer, stroke and fibrosis. However, the neuroprotective potency of noscapine has not been analyzed. Our study showed that administration of noscapine decreased the upregulation of pro-inflammatory factors, oxidative stress, and α-synuclein expression with a significant increase in antioxidant enzymes. In addition, noscapine prevented rotenone-induced activation of microglia and astrocytes. These neuroprotective mechanisms resulted in a decrease in dopaminergic neuron loss in SNpc and neuronal fibers in the striatum. Further, noscapine administration enhanced the mTOR-mediated p70S6K pathway as well as inhibited apoptosis. In addition to these mechanisms, noscapine prevented a rotenone-mediated increase in lysosomal degradation, resulting in a decrease in α-synuclein aggregation. However, further studies are needed to further develop noscapine as a potential therapeutic candidate for PD treatment.

Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra

2007 ◽  
Vol 0 (0) ◽  
pp. 070214184024010-??? ◽  
Author(s):  
Jessie L. St Martin ◽  
Jochen Klucken ◽  
Tiago F. Outeiro ◽  
Paul Nguyen ◽  
Christine Keller-McGandy ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Dopaminergic Neuron ◽  
Alpha Synuclein ◽  
Neuron Loss ◽  
Over Expression ◽  
Chaperone Protein ◽  
Dopaminergic Neuron Loss

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.

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