Expression of peroxisome proliferator-activated receptor-gamma in the substantia nigra of hemiparkinsonian nonhuman primates

Swanson, Christine R.; Emborg, Marina E.

doi:10.1179/1743132813y.0000000305

Cited by 27 publications

(17 citation statements)

References 33 publications

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“…In nonhuman primates, PPAR-γ expression is prominent in the subthalamic nucleus, oculomotor nucleus, VTA, and, to a lesser extent, in the putamen [65]. PPAR-γ agonists pioglitazone and rosiglitazone have anti-inflammatory and anti-oxidative properties [66].…”

Section: Discussionmentioning

confidence: 99%

High Fat Diet Suppresses Peroxisome Proliferator-Activated Receptors and Reduces Dopaminergic Neurons in the Substantia Nigra

Kao

Wei

Tsai

et al. 2019

IJMS

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Although several epidemiologic and animal studies have revealed correlations between obesity and neurodegenerative disorders, such as Parkinson disease (PD), the underlying pathological mechanisms of obesity-induced PD remain unclear. Our study aimed to assess the effect of diet-induced obesity on the brain dopaminergic pathway. For five months, starting from weaning, we gave C57BL/6 mice a high-fat diet (HFD) to generate an obese mouse model and investigate whether the diet reprogrammed the midbrain dopaminergic system. Tyrosine hydroxylase staining showed that the HFD resulted in fewer dopaminergic neurons in the substantia nigra (SN), but not the striatum. It also induced neuroinflammation, with increased astrogliosis in the SN and striatum. Dendritic spine density in the SN of HFD-exposed mice decreased, which suggested that prolonged HFD altered dopaminergic neuroplasticity. All three peroxisome proliferator-activated receptor (PPAR) subtype (PPAR-α, PPAR-β/δ, PPAR-γ) levels were significantly reduced in the SN and the ventral tegmental area of HFD mice when compared to those in controls. This study showed that a prolonged HFD induced neuroinflammation, suppressed PPAR levels, caused degeneration of midbrain dopaminergic neurons, and resulted in symptoms reminiscent of human PD. To our knowledge, this is the first study documenting the effects of an HFD on PPARs in dopaminergic neurons.

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Section: Discussionmentioning

confidence: 99%

High Fat Diet Suppresses Peroxisome Proliferator-Activated Receptors and Reduces Dopaminergic Neurons in the Substantia Nigra

Kao

Wei

Tsai

et al. 2019

IJMS

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“…The nuclei were identified using a microscope Nikon Eclipse 800 and a stereotaxic atlas as reference [27]. Protein expression was classified using a modified rating scale [28] as: (−) not detected, (±) minimal (only few positive cells or fibers are found), (+) moderate (<25% of the nucleus is covered by strong immunoreactivity, (++) intense (<50% of the nucleus is covered by strong immunoreactivity) and (+++) very intense (>50% of the nucleus is covered by strong immunoreactivity).…”

Section: Methodsmentioning

confidence: 99%

Titer and Product Affect the Distribution of Gene Expression after Intraputaminal Convection-Enhanced Delivery

Emborg¹,

Hurley

Joers³

et al. 2014

Stereotact Funct Neurosurg

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Background: The efficacy and safety of intracerebral gene therapy for brain disorders like Parkinson's disease depends on the appropriate distribution of gene expression. Objectives: To assess whether the distribution of gene expression is affected by vector titer and protein type. Methods: Four adult macaque monkeys seronegative for adeno-associated virus 5 (AAV5) received a 30-µl inoculation of a high- or a low-titer suspension of AAV5 encoding glial cell line-derived neurotrophic factor (GDNF) or green fluorescent protein (GFP) in the right and left ventral postcommissural putamen. The inoculations were conducted using convection-enhanced delivery and intraoperative MRI (IMRI). Results: IMRI confirmed targeting and infusion cloud irradiation from the catheter tip into the surrounding area. A postmortem analysis 6 weeks after surgery revealed GFP and GDNF expression ipsilateral to the injection site that had a titer-dependent distribution. GFP and GDNF expression was also observed in fibers in the substantia nigra (SN) pars reticulata (pr), demonstrating anterograde transport. Few GFP-positive neurons were present in the SN pars compacta (pc), possibly by direct retrograde transport of the vector. GDNF was present in many neurons of the SNpc and SNpr. Conclusions: After controlling for target and infusate volume, the intracerebral distribution of the gene product was affected by the vector titer and product biology.

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“…The thiazolidinediones are a class of drugs that increase insulin sensitivity by acting as selective ligands of the peroxisome proliferator-activated receptor gamma (PPARγ) receptor. PPARγ receptors are expressed in insulin sensitive tissues such as liver and pancreas, but are also expressed in nigral and putaminal nuclei (Swanson and Emborg, 2014). Two drugs of this class, rosiglitazone and pioglitazone have been used as insulin sensitizing agents for the treatment of non-insulin dependent diabetes (Leonardini et al, 2009).…”

Section: Thiazolidinedionesmentioning

confidence: 99%

Insulin resistance and Parkinson’s disease: A new target for disease modification?

Athauda

Foltynie

2016

Progress in Neurobiology

260

209

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There is growing evidence that patients with Type 2 diabetes have an increased risk of developing Parkinson's disease and share similar dysregulated pathways suggesting common underlying pathological mechanisms. Historically insulin was thought solely to be a peripherally acting hormone responsible for glucose homeostasis and energy metabolism. However accumulating evidence indicates insulin can cross the blood-brain-barrier and influence a multitude of processes in the brain including regulating neuronal survival and growth, dopaminergic transmission, maintenance of synapses and pathways involved in cognition. In conjunction, there is growing evidence that a process analogous to peripheral insulin resistance occurs in the brains of Parkinson's disease patients, even in those without diabetes. This raises the possibility that defective insulin signalling pathways may contribute to the development of the pathological features of Parkinson's disease, and thereby suggests that the insulin signalling pathway may potentially be a novel target for disease modification. Given these growing links between PD and Type 2 diabetes it is perhaps not unsurprising that drugs used the treatment of T2DM are amongst the most promising treatments currently being prioritised for repositioning as possible novel treatments for PD and several clinical trials are under way. In this review, we will examine the underlying cellular links between insulin resistance and the pathogenesis of PD and then we will assess current and future pharmacological strategies being developed to restore neuronal insulin signalling as a potential strategy for slowing neurodegeneration in Parkinson's disease.

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Expression of peroxisome proliferator-activated receptor-gamma in the substantia nigra of hemiparkinsonian nonhuman primates

Cited by 27 publications

References 33 publications

High Fat Diet Suppresses Peroxisome Proliferator-Activated Receptors and Reduces Dopaminergic Neurons in the Substantia Nigra

High Fat Diet Suppresses Peroxisome Proliferator-Activated Receptors and Reduces Dopaminergic Neurons in the Substantia Nigra

Titer and Product Affect the Distribution of Gene Expression after Intraputaminal Convection-Enhanced Delivery

Insulin resistance and Parkinson’s disease: A new target for disease modification?

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