Parkinson';s Disease, Diabetes and Cognitive Impairment

Ashraghi, Mohammad R.; Pagano, Gennaro; Polychronis, Sotirios; Niccolini, Flavia; Politis, Marios

doi:10.2174/1872214810999160628105549

Cited by 55 publications

(26 citation statements)

References 88 publications

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“…High levels of systemic TNFα can cross the blood-brain barrier (BBB), stimulating the microglia to secrete more TNFα as well as other proinflammatory factors and thus creating persistent and self-generated neuroinflammation [15]. Metabolic diseases such as obesity, hypertension, dyslipidemia, diabetes, and insulin resistance are associated with chronic systemic inflammation and a higher risk of developing neurodegenerative diseases such as Alzheimer's disease and PD [17][18][19][20][21][22][23]. Due to the importance of peripheral inflammatory processes in PD development [24][25][26], it is relevant to investigate more thoroughly the mechanisms involved.…”

Section: Introductionmentioning

confidence: 99%

Chronic Systemic Inflammation Exacerbates Neurotoxicity in a Parkinson’s Disease Model

Ugalde‐Muñiz

Fetter-Pruneda

Navarro

et al. 2020

Oxidative Medicine and Cellular Longevity

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Systemic inflammation is a crucial factor for microglial activation and neuroinflammation in neurodegeneration. This work is aimed at assessing whether previous exposure to systemic inflammation potentiates neurotoxic damage by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and how chronic systemic inflammation participates in the physiopathological mechanisms of Parkinson’s disease. Two different models of systemic inflammation were employed to explore this hypothesis: a single administration of lipopolysaccharide (sLPS; 5 mg/kg) and chronic exposure to low doses (mLPS; 100 μg/kg twice a week for three months). After three months, both groups were challenged with MPTP. With the sLPS administration, Iba1 staining increased in the striatum and substantia nigra, and the cell viability lowered in the striatum of these mice. mLPS alone had more impact on the proinflammatory profile of the brain, steadily increasing TNFα levels, activating microglia, reducing BDNF, cell viability, and dopamine levels, leading to a damage profile similar to the MPTP model per se. Interestingly, mLPS increased MAO-B activity possibly conferring susceptibility to MPTP damage. mLPS, along with MPTP administration, exacerbated the neurotoxic effect. This effect seemed to be coordinated by microglia since minocycline administration prevented brain TNFα increase. Coadministration of sLPS with MPTP only facilitated damage induced by MPTP without significant change in the inflammatory profile. These results indicate that chronic systemic inflammation increased susceptibility to MPTP toxic effect and is an adequate model for studying the impact of systemic inflammation in Parkinson’s disease.

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Section: Introductionmentioning

confidence: 99%

Chronic Systemic Inflammation Exacerbates Neurotoxicity in a Parkinson’s Disease Model

Ugalde‐Muñiz

Fetter-Pruneda

Navarro

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Lewy bodies, neurofibrillary tangles (NFTs) and senile plaques may all contribute to the heterogeneous cellular pathology observed in cases of PDD (Wang et al, 2010 ). Interestingly, one of the most important recent findings is the link between PDD pathogenesis and the mechanisms underlying the development of insulin resistance; studies have found that patients with PDD are prone to comorbid insulin resistance (Bosco et al, 2012 ; Ashraghi et al, 2016 ), even when they were unaffected by Diabetes Mellitus. Furthermore, it has proven that Diabetes Mellitus increases the risk of developing Alzheimer's disease (AD).…”

Section: Introductionmentioning

confidence: 99%

The Role of Insulin/IGF-1/PI3K/Akt/GSK3β Signaling in Parkinson's Disease Dementia

et al. 2018

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Dementia, a condition that frequently afflicts patients in advanced stages of Parkinson's disease (PD), results in decreased quality of life and survival time. Nevertheless, the pathological mechanisms underlying Parkinson's disease dementia (PDD) are not completely understood. The symptoms characteristic of PDD may be the result of functional and structural deficiencies. The present study implicates the accumulation of Lewy bodies in the cortex and limbic system as a potent trigger in the development of PDD. In addition, significant Alzheimer-type pathologies, including amyloid-β (Aβ) plaques and NFTs, are observed in almost half of PDD patients. Interestingly, links between PDD pathogenesis and the mechanisms underlying the development of insulin resistance have begun to emerge. Furthermore, previous studies have demonstrated that insulin treatment reduces amyloid plaques in Alzheimer's disease (AD), and normalizes the production and functionality of dopamine and ameliorates motor impairments in 6-OHDA-induced rat PD models. GSK3β, a downstream substrate of PI3K/Akt signaling following induction by insulin and IGF-1, exerts an influence on AD and PD physiopathology. The genetic overexpression of GSK3β in cortex and hippocampus results in signs of neurodegeneration and spatial learning deficits in in vivo models (Lucas et al., 2001), whereas its inhibition results in improvements in cognitive impairment in these rodents, including AD and PD. Accordingly, insulin- or IGF-1-activated PI3K/Akt/GSK3β signaling may be involved in PDD pathogenesis, at least in the pathology of PD-type + AD-type.

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“…GLP-1 agonists are well established as effective agents to treat patients with T2DM due to a range of beneficial actions including weight loss, induction of satiety, inhibition of gastric emptying, stimulation of insulin secretion and inhibition of alpha cell function (Bailey et al 2016). In addition, GLP-1 agonists exert effects at other extra pancreatic sites (Renner et al 2016), with notable neuroprotective actions in animal models of diabetes-obesity, Alzheimer's disease (AD) and Parkinson's disease (PD) (Ashraghi et al 2016, Tramutola et al 2017. Liraglutide (Victoza) is a highly effective long-acting GLP-1 agonist that shares 97% sequence homology with human GLP-1 (Knudsen et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice

Millar

Pathak

Parthsarathy

et al. 2017

Journal of Endocrinology

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This study assessed the metabolic and neuroprotective actions of the sodium glucose cotransporter-2 inhibitor dapagliflozin in combination with the GLP-1 agonist liraglutide in dietary-induced diabetic mice. Mice administered low-dose streptozotocin (STZ) on a high-fat diet received dapagliflozin, liraglutide, dapagliflozin-plus-liraglutide (DAPA-Lira) or vehicle once-daily over 28 days. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin sensitivity, hormone and biochemical analysis, dual-energy X-ray absorptiometry densitometry, novel object recognition, islet and brain histology were examined. Once-daily administration of DAPA-Lira resulted in significant decreases in body weight, fat mass, glucose and insulin concentrations, despite no change in energy intake. Similar beneficial metabolic improvements were observed regarding glucose tolerance, insulin sensitivity, HOMA-IR, HOMA-β, HbA1c and triglycerides. Plasma glucagon, GLP-1 and IL-6 levels were increased and corticosterone concentrations decreased. DAPA-Lira treatment decreased alpha cell area and increased insulin content compared to dapagliflozin monotherapy. Recognition memory was significantly improved in all treatment groups. Brain histology demonstrated increased staining for doublecortin (number of immature neurons) in dentate gyrus and synaptophysin (synaptic density) in stratum oriens and stratum pyramidale. These data demonstrate that combination therapy of dapagliflozin and liraglutide exerts beneficial metabolic and neuroprotective effects in diet-induced diabetic mice. Our results highlight important personalised approach in utilising liraglutide in combination with dapagliflozin, instead of either agent alone, for further clinical evaluation in treatment of diabetes and associated neurodegenerative disorders.

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Parkinson';s Disease, Diabetes and Cognitive Impairment

Cited by 55 publications

References 88 publications

Chronic Systemic Inflammation Exacerbates Neurotoxicity in a Parkinson’s Disease Model

Chronic Systemic Inflammation Exacerbates Neurotoxicity in a Parkinson’s Disease Model

The Role of Insulin/IGF-1/PI3K/Akt/GSK3β Signaling in Parkinson's Disease Dementia

Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice

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