Metformin as a Potential Neuroprotective Agent in Prodromal Parkinson's Disease—Viewpoint

Sportelli, Carolina; Urso, Daniele; Jenner, Peter

doi:10.3389/fneur.2020.00556

Cited by 33 publications

(25 citation statements)

References 143 publications

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“…In addition, previous data based on systemic glucose injections in rats also show an inhibitory effect on the firing of SN DA neurons [ 6 ]. Type II diabetes characterized by increased blood glucose and insulin resistance seems to increase the risk to develop Parkinson’s disease (PD), an age-related neurodegenerative disease in which SN DA neurons are progressively lost [ 7 , 8 ]. Several studies indicate a ciliary role in the function of the dopamine system.…”

Section: Introductionmentioning

confidence: 99%

Targeted Ablation of Primary Cilia in Differentiated Dopaminergic Neurons Reduces Striatal Dopamine and Responsiveness to Metabolic Stress

et al. 2021

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Primary cilia (PC) are microtubule-based protrusions of the cell membrane transducing molecular signals during brain development. Here, we report that PC are required for maintenance of Substantia nigra (SN) dopaminergic (DA) neurons highly vulnerable in Parkinson’s disease (PD). Targeted blockage of ciliogenesis in differentiated DA neurons impaired striato-nigral integrity in adult mice. The relative number of SN DA neurons displaying a typical auto-inhibition of spontaneous activity in response to dopamine was elevated under control metabolic conditions, but not under metabolic stress. Strikingly, in the absence of PC, the remaining SN DA neurons were less vulnerable to the PD neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP). Our data indicate conserved PC-dependent neuroadaptive responses to DA lesions in the striatum. Moreover, PC control the integrity and dopamine response of a subtype of SN DA neurons. These results reinforce the critical role of PC as sensors of metabolic stress in PD and other disorders of the dopamine system.

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Section: Introductionmentioning

confidence: 99%

Targeted Ablation of Primary Cilia in Differentiated Dopaminergic Neurons Reduces Striatal Dopamine and Responsiveness to Metabolic Stress

et al. 2021

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“…Furthermore, a recent meta-analysis found an association of type-2 diabetes with PD and some evidence for an increased progression of motor symptoms and cognitive decline ( 36 ). First studies showed a potential effect of anti-diabetic drugs on the progression of PD ( 37 ). Notably, diabetes was associated with the heterozygous PRKN mutation carrier status in our study.…”

Section: Discussionmentioning

confidence: 99%

Frequency of Heterozygous Parkin (PRKN) Variants and Penetrance of Parkinson's Disease Risk Markers in the Population-Based CHRIS Cohort

et al. 2021

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Mutations in the Parkin (PRKN) gene are the most frequent cause of autosomal recessive early-onset Parkinson's disease (PD). Heterozygous PRKN mutation carriers might also be at increased risk for developing clinical symptoms of PD. Given the high frequency of heterozygous mutations in the general population, it is essential to have better estimates of the penetrance of these variants, and to investigate, which clinical and biochemical markers are present in carriers and thus potentially useful for identifying those individuals at greater risk of developing clinical symptoms later in life. In the present study, we ascertained the frequency of heterozygous PRKN mutation carriers in a large population sample of the Cooperative Health Research in South Tyrol (CHRIS) study, and screened for reported PD risk markers. 164 confirmed heterozygous PRKN mutation carriers were compared with 2,582 controls. A higher number of heterozygous mutation carriers reported a detectable increase in an akinesia-related phenotype, and a higher percentage of carriers had manifested diabetes. We also observed lower resting heart rate in the PRKN mutation carriers. Extending our risk analyses to a larger number of potential carriers and non-carriers using genotype imputation (n = 299 carriers and n = 7,127 non-carriers), from previously published biomarkers we also observed a higher neutrophil-to-lymphocyte ratio (NLR) and lower serum albumin and sodium levels in the heterozygous PRKN variant carriers. These results identify a set of biomarkers that might be useful either individually or as an ensemble to identify variant carriers at greater risk of health issues due to carrier status.

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“…In addition, rodent studies indicate that chronic use of metformin prevents the adverse effects of aging and increases life expectancy [13,14], and data from a meta-analysis confirms decreased risk of Parkinson's disease in combination with sulfonylurea derivatives [15]. As it was previously demonstrated, the effects of metformin occur are attributed to the AMP-activated protein kinase (AMPK) activation and phosphorylation followed by increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression [1,16] of muscle coordination and activity [17]. In vitro models show that metformin is able to stop the apoptotic process via AMPK pathway [18], being a possible therapeutic target in neurodegenerative diseases [7].…”

Section: Introductionmentioning

confidence: 90%

“…Contrary to the fact that progreses have been made in the medical field, due to the complex physiology of the brain, for many of the mental disorders, pharmacological approaches could not meet the therapeutic needs [1]. In the case of schizophrenia but also in other neurotic disorders, despite the development of modern neuroleptics, one of the most widely used antipsychotics remains haloperidol given its low costs and high potency [2].…”

Section: Introductionmentioning

confidence: 99%

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Beneficial effects of metformin on haloperidol-induced motor deficits in rats. A behavioral assessment

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et al. 2021

Acta Marisiensis - Seria Medica

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Objective: One of the most common side effects of haloperidol is the extrapyramidal syndrome, resulting from inhibition of nigrostriatal dopaminergic circuits and mitochondrial dysfunction due to structural similarities to pyridinium derivative, MPP+ that induce oxidative stress. In exchange, the use of metformin appears to enhance neurogenesis, energy metabolism, and oxidative status, so these properties can be speculated in the context of drug-induced pseudoparkinsonism by haloperidol. Methods: To assess motor coordination and activity, rodents were divided into four groups: CTR (n = 10) - animals that received distilled water, METF (n = 10) - animals that received metformin 500 mg / kgbw, HAL (n = 10) - animals that received haloperidol 2mg / kgbw, HALMETF (n = 10) - haloperidol 2mg / kgbw and metformin 500 mg / kgbw. The treatment was administered for 34 days at the same time by gastric gavage, during which time behavioral tests, rotarod (days 7, 14, 21, 28), catalepsy (day 30), open field (day 32) and novel object recognition (day 34) were performed. Results: The monitored parameters, showed significant differences between the groups of interest (HAL and HALMETF respectively), so that the administration of metformin at the beginning of treatment reduces the cataleptic behavior. The HALMETF group shows an attenuation of the motor deficit during the rotarod test and the freezing period from the Open Field test, is diminished. Conclusions: Metformin treatment has a beneficial effect in haloperidol-treated rats, demonstrated by decreased cataleptic behavior, improved motor performance and reduced haloperidol-induced anxiety behavior.

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Metformin as a Potential Neuroprotective Agent in Prodromal Parkinson's Disease—Viewpoint

Cited by 33 publications

References 143 publications

Targeted Ablation of Primary Cilia in Differentiated Dopaminergic Neurons Reduces Striatal Dopamine and Responsiveness to Metabolic Stress

Targeted Ablation of Primary Cilia in Differentiated Dopaminergic Neurons Reduces Striatal Dopamine and Responsiveness to Metabolic Stress

Frequency of Heterozygous Parkin (PRKN) Variants and Penetrance of Parkinson's Disease Risk Markers in the Population-Based CHRIS Cohort

Beneficial effects of metformin on haloperidol-induced motor deficits in rats. A behavioral assessment

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