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.
    Full-text · Article · Oct 2015 · Neuropharmacology
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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.
    Full-text · Article · Jul 2015 · Neurology Research International
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    • "Malnutrition has relevant consequences on some metabolic parameters closely related to Parkinson's disease (PD) pathogenesis , among which chronic systemic inflammation [1], oxidative stress [2], plasma homocysteine levels [3], and, especially, insulin resistance [4]. An increasing number of evidence suggests a close relationship between insulin resistance and dopaminergic degeneration [4]. Also, it should be considered that some drugs used to treat PD, like L-dopa itself, can induce both hyperglycemia and hyperinsulinemia [5]. "
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    ABSTRACT: The correlation between Parkinson disease and malnutrition is well established, however a protein-restricted diet is usually prescribed because of potentially negative interactions between dietary amino acids and l-dopa pharmacokinetics. This strategy could increase the risk of further nutritional deficits. A monocentric, prospective, randomized, double-blind pilot study was performed on two groups of Parkinson-affected, protein-restricted, patients: Intervention (n = 7; amino acid supplementation twice daily) and Placebo (n = 7; placebo supplementation twice daily). At enrolment, after 3- and 6-month supplementation, neurological evaluations (UPDRS III, Hoenh-Yahr scale, l-dopa equivalent dose assessment) were performed and blood sample was collected to define insulin sensitivity (QUICKI index) and oxidative stress (oxidized and reduced glutathione). Repeated measure ANCOVA was applied to define time effect and time × treatment interaction. Participants were comparable at baseline for all assessed parameters. Neurological outcomes and l-dopa requirement were comparable in both group after 6-month of supplementation, without time × treatment interaction. The decrease in insulin sensitivity, as assessed by QUICKI index, observed after 6 months in both groups, was greater in Placebo than in Intervention (time effect p < 0.001; time × treatment interaction p = 0.01). Moreover, despite no changes in total erythrocyte glutathione concentrations, oxidized glutathione levels decreased by 28 ± 17% in the Intervention while increased by 55 ± 38% in Placebo (time effect p = 0.05; time × treatment interaction p = 0.05), after 6-month supplementation. Amino acid supplementation, assumed with shrewd temporal distribution, did not show detrimental effects on neurological and pharmacological control in protein-restricted Parkinson-affected patients, chronically treated with l-dopa. Furthermore, daily amino acid supplementation partially counteracted insulin resistance development and the loss in antioxidant availability. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
    Full-text · Article · Dec 2014 · Clinical nutrition (Edinburgh, Scotland)
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