Parkinson’s disease, insulin resistance and novel agents of neuroprotection

1 Sobell Department of Motor Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Brain (Impact Factor: 9.2). 02/2012; 136(2). DOI: 10.1093/brain/aws009
Source: PubMed


Multiple avenues of research including epidemiology, molecular genetics and cell biology have identified links between Parkinson's disease and type 2 diabetes mellitus. Several recent discoveries have highlighted common cellular pathways that potentially relate neurodegenerative processes with abnormal mitochondrial function and abnormal glucose metabolism. This includes converging evidence identifying that peroxisome proliferator activated receptor gamma coactivator 1-α, a key regulator of enzymes involved in mitochondrial respiration and insulin resistance, is potentially pivotal in the pathogenesis of neurodegeneration in Parkinson's disease. This evidence supports further study of these pathways, most importantly to identify neuroprotective agents for Parkinson's disease, and/or establish more effective prevention or treatment for type 2 diabetes mellitus. In parallel with these advances, there are already randomized trials evaluating several established treatments for insulin resistance (pioglitazone and exenatide) as possible disease modifying drugs in Parkinson's disease, with only preliminary insights regarding their mechanisms of action in neurodegeneration, which may be effective in both disease processes through an action on mitochondrial function. Furthermore, parallels are also emerging between these same pathways and neurodegeneration associated with Alzheimer's disease and Huntington's disease. Our aim is to highlight this converging evidence and stimulate further hypothesis-testing studies specifically with reference to the potential development of novel neuroprotective agents in Parkinson's disease.

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Available from: Iciar Aviles-Olmos, Apr 15, 2014
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    • "In light of these recent findings, a hypothesis has emerged that suggests that mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, and alterations in metabolism may lead to insulin resistance and, ultimately, to diabetes and/or neurodegeneration (Lima et al., 2014; Santiago and Potashkin, 2013). Hence, the treatment to improve insulin resistance for T2DM may be useful for PD patients (Aviles-­‐Olmos et al., 2013b; Holscher, 2014b). "
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    ABSTRACT: Parkinson's disease (PD) is a chronic neurodegenerative disease, and there is no cure for it at present. Recent research has indicated a link between type 2 diabetes mellitus (T2DM) and PD, which suggested that a treatment to improve insulin resistance for T2DM may be useful for PD patients. Glucose-dependent insulinotropic polypeptide (GIP) belongs to the incretin hormone family, which can promote insulin release and improve insulin resistance. Several GIP analogues have been developed as potential treatments for T2DM. In the present study, a novel long-lasting GIP analogue, D-Ala2-GIP-glu-PAL, has been tested in an acute PD mouse model induced by four 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneal injections. D-Ala2-GIP-glu-PAL treatment (25nmol/kg ip.) for 7 days after MPTP treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement balance of mice. D-Ala2-GIP-glu-PAL treatment also restored tyrosine hydroxylase (TH) positive dopaminergic neuron numbers in the substantia nigra and TH levels in the striatum. D-Ala2-GIP-glu-PAL also reduced the chronic inflammation response as seen in astrocyte and microglia activation in the substantia nigra pars compacta (SNpc). D-Ala2-GIP-glu-PAL reversed the reduction of synapse numbers (synaptophysin levels), decreased the ratio of growth factor and apoptosis signaling molecules Bax/Bcl-2, and improved the decrease of p-CREB(S133) growth factor signaling in the substantia nigra. Therefore, D-Ala2-GIP-glu-PAL promotes cell survival of dopaminergic neuron in the SNpc by activating the cAMP/PKA/CREB growth factor second messenger pathway that also inhibits apoptosis. The present results demonstrate that D-Ala2-GIP-glu-PAL shows promise as a novel treatment of PD.
    Neuropharmacology 10/2015; 101. DOI:10.1016/j.neuropharm.2015.10.002 · 5.11 Impact Factor
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    • "suggested that these receptor agonists may improve some of the histopathological features of Parkinson's disease, optic nerve crush, and spinal nerve crush and cerebral ischemia [7] [8] [9]. It has been shown that activation of PPAR induces anti-inflammatory and antioxidant properties in brain. "
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    ABSTRACT: The objective was evaluation of the effects of pioglitazone on medial prefrontal cortex (mPFC) of the rats exposed to aluminum (Al). Al induces structural changes in several brain regions, including mPFC. Pioglitazone is an agonist of peroxisomal proliferator activated receptor gamma. Male rats were randomly assigned to control, Al-treated (10 mg/kg/day), and Al + PIO-treated groups (Al+ 40 mg/kg/day). After 56 days, the right mPFCs were removed. Then, the volume of mPFC and its subdivisions, volume of vessels, and total number of neurons and glia were estimated using stereological methods. The results showed 13-38% decrease in the volume of the mPFC and its subdivisions, mainly in the infralimbic region (). Besides, the volume of the vessels reduced by 47% after Al-treatment (). The total number of the neurons and glial cells was also reduced (40% and 25%, resp.) in the Al-exposed rats in comparison to the control ones (). Treatment of the animals with Al + PIO ameliorated the neuron loss and no improvement was seen in other parameters (). It can be concluded that treatment of the rats with PIO could ameliorate the neuron loss in the mPFC of the Al-treated animals.
    Neurology Research International 07/2015; 2015:1-8. DOI:10.1155/2015/381934
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    • "T2DM contributes to postural instability and gait difficulty in PD [10] and insulin resistance is associated with an increased risk of dementia in PD [11]. Besides insulin resistance, dysregulation in other shared biological pathways including mitochondrial dysfunction, endoplasmic reticulum (ER) stress and inflammation may be a plausible explanation for the coexistence of both aging diseases [4], [12]. "
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    ABSTRACT: Increasing evidence indicates that Parkinson's disease (PD) and type 2 diabetes (T2DM) share dysregulated molecular networks. We identified 84 genes shared between PD and T2DM from curated disease-gene databases. Nitric oxide biosynthesis, lipid and carbohydrate metabolism, insulin secretion and inflammation were identified as common dysregulated pathways. A network prioritization approach was implemented to rank genes according to their distance to seed genes and their involvement in common biological pathways. Quantitative polymerase chain reaction assays revealed that a highly ranked gene, superoxide dismutase 2 (SOD2), is upregulated in PD patients compared to healthy controls in 192 whole blood samples from two independent clinical trials, the Harvard Biomarker Study (HBS) and the Diagnostic and Prognostic Biomarkers in Parkinson's disease (PROBE). The results from this study reinforce the idea that shared molecular networks between PD and T2DM provides an additional source of biologically meaningful biomarkers. Evaluation of this biomarker in de novo PD patients and in a larger prospective longitudinal study is warranted.
    PLoS ONE 10/2014; 9(10):e109042. DOI:10.1371/journal.pone.0109042 · 3.23 Impact Factor
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