The beneficial effect of salubrinal on neuroinflammation and neuronal loss in intranigral LPS-induced hemi-Parkinson disease model in rats

Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced Parkinson’s disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2–related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell–derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.

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Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

ASN NEURO ◽

10.1177/17590914211009730 ◽

2021 ◽

Vol 13 ◽

pp. 175909142110097

Author(s):

Kui Cui ◽

Fan Yang ◽

Turan Tufan ◽

Muhammad U. Raza ◽

Yanqiang Zhan ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Transcription Factors ◽

Disease Model ◽

Neuronal Loss ◽

Mrna Levels ◽

Gene Therapies ◽

Protein Levels ◽

Dopaminergic Systems ◽

And Function

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.

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2.414 Glutathione system in rotenone induced Parkinson disease model: Improvement by co-treatment of centrophenoxine

Parkinsonism & Related Disorders ◽

10.1016/s1353-8020(08)70734-x ◽

2007 ◽

Vol 13 ◽

pp. S131

Author(s):

B. Nehru ◽

R. Verma

Keyword(s):

Parkinson Disease ◽

Disease Model ◽

Glutathione System ◽

Model Improvement

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PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1606171113 ◽

2016 ◽

Vol 113 (43) ◽

pp. 12292-12297 ◽

Cited By ~ 46

Author(s):

Loukia Katsouri ◽

Yau M. Lim ◽

Katrin Blondrath ◽

Ioanna Eleftheriadou ◽

Laura Lombardero ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pyramidal Neurons ◽

Lentiviral Vector ◽

Disease Model ◽

Amyloid Β ◽

Neuronal Loss ◽

Peroxisome Proliferator ◽

Neuroprotective Effects ◽

Peroxisome Proliferator Activated Receptor

Current therapies for Alzheimer’s disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.

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The Benefit of Subthalamic Deep Brain Stimulation for Pain in Parkinson Disease: A 2-Year Follow-up Study

Neurosurgery ◽

10.1227/neu.0b013e3182266664 ◽

2011 ◽

Vol 70 (1) ◽

pp. 18-24 ◽

Cited By ~ 37

Author(s):

Han-Joon Kim ◽

Beom S. Jeon ◽

Jee-Young Lee ◽

Sun Ha Paek ◽

Dong Gyu Kim

Keyword(s):

Deep Brain Stimulation ◽

Beneficial Effect ◽

Parkinson Disease ◽

Brain Stimulation ◽

Rating Scale ◽

Motor Disorder ◽

Motor Symptoms ◽

Stn Dbs ◽

Deep Brain

Abstract BACKGROUND Pain is a well-recognized feature of Parkinson disease (PD), which is primarily a motor disorder. In a previous study, we showed that subthalamic deep brain stimulation (STN DBS) improves pain as well as motor symptoms 3 months after surgery in PD patients. OBJECTIVE To determine whether there is a long-term beneficial effect of STN DBS on pain in PD. METHODS We studied 21 patients with PD who underwent STN DBS. Motor symptoms were assessed using the Unified Parkinson's Disease Rating Scale and Hoehn and Yahr staging. Pain was evaluated by asking patients about the quality and severity of pain in each body part. Evaluations were performed at baseline and at 3 and 24 months after surgery. RESULTS At baseline, 18 of the 21 patients (86%) experienced pain. After surgery, most of the pain reported at baseline had improved or disappeared at 3 months and improved further at 24 months. The benefit of STN DBS for pain evaluated at 24 months was comparable to that with medication at baseline. At 24 months, 9 patients (43%) reported new pain that was not present at baseline. Most of the new pain was musculoskeletal in quality. Despite the development of new pain, the mean pain score at follow-up was lower than at baseline. CONCLUSION STN DBS improves pain in PD, and this beneficial effect persists, being observed after a prolonged follow-up of 24 months. In addition, in many of the PD patients new, mainly musculoskeletal pain developed on longer follow-up.

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Manganese Inhalation as a Parkinson Disease Model

Parkinson s Disease ◽

10.4061/2011/612989 ◽

2011 ◽

Vol 2011 ◽

pp. 1-14 ◽

Cited By ~ 7

Author(s):

José Luis Ordoñez-Librado ◽

Verónica Anaya-Martínez ◽

Ana Luisa Gutierrez-Valdez ◽

Laura Colín-Barenque ◽

Enrique Montiel-Flores ◽

...

Keyword(s):

Parkinson Disease ◽

Disease Model ◽

Manganese Acetate ◽

Male Mice ◽

Behavioral Alterations ◽

Action Tremor ◽

Dopaminergic Cell ◽

Dopamine Content ◽

Motor Disturbances ◽

Motor Alterations

The present study examines the effects of divalent and trivalent Manganese (Mn2+/Mn3+) mixture inhalation on mice to obtain a novel animal model of Parkinson disease (PD) inducing bilateral and progressive dopaminergic cell death, correlate those alterations with motor disturbances, and determine whetherL-DOPA treatment improves the behavior, to ensure that the alterations are of dopaminergic origin. CD-1 male mice inhaled a mixture of Manganese chloride and Manganese acetate, one hour twice a week for five months. Before Mn exposure, animals were trained to perform motor function tests and were evaluated each week after the exposure. By the end of Mn exposure, 10 mice were orally treated with 7.5 mg/kgL-DOPA. After 5 months of Mn mixture inhalation, striatal dopamine content decreased 71%, the SNc showed important reduction in the number of TH-immunopositive neurons, mice developed akinesia, postural instability, and action tremor; these motor alterations were reverted withL-DOPA treatment. Our data provide evidence that Mn2+/Mn3+mixture inhalation produces similar morphological, neurochemical, and behavioral alterations to those observed in PD providing a useful experimental model for the study of this neurodegenerative disease.

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