Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges

Agostini, Francesco; Masato, Anna; Bubacco, Luigi; Bisaglia, Marco

doi:10.3390/ijms23010398

Cited by 43 publications

(31 citation statements)

References 97 publications

(140 reference statements)

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“…We will further determine whether the combined effect of two or more drugs is equal to the sum of the effect of each drug given alone. Previous studies have documented that taking metformin for a long time might lead to vitamin B12 deficiency and anemia in non-diabetic patients ( 69 ). Moreover, the safety of taking rapamycin remains controversial up to now ( 70 ).…”

Section: Discussionmentioning

confidence: 99%

Metformin, Rapamycin, or Nicotinamide Mononucleotide Pretreatment Attenuate Cognitive Impairment After Cerebral Hypoperfusion by Inhibiting Microglial Phagocytosis

Zheng

Cheng

et al. 2022

Front. Neurol.

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Vascular cognitive impairment (VCI) is the second leading form of dementia after Alzheimer's disease (AD) plaguing the elder population. Despite the enormous prevalence of VCI, the biological basis of this disease has been much less well-studied than that of AD, with no specific therapy currently existing to prevent or treat VCI. As VCI mainly occurs in the elderly, the role of anti-aging drugs including metformin, rapamycin, and nicotinamide mono nucleotide (NMN), and the underlying mechanism remain uncertain. Here, we examined the role of metformin, rapamycin, and NMN in cognitive function, white matter integrity, microglial response, and phagocytosis in a rat model of VCI by bilateral common carotid artery occlusion (BCCAO). BCCAO-induced chronic cerebral hypoperfusion could cause spatial working memory deficits and white matter lesions (WMLs), along with increasing microglial activation and phagocytosis compared to sham-operated rats. We found the cognitive impairment was significantly improved in BCCAO rats pretreated with these three drugs for 14 days before BCCAO compared with the vehicle group by the analysis of the Morris water maze and new object recognition tests. Pretreatment of metformin, rapamycin, or NMN also increased myelin basic protein (MBP, a marker for myelin) expression and reduced SMI32 (a marker for demyelinated axons) intensity and SMI32/MBP ratio compared with the vehicle group, suggesting that these drugs could ameliorate BCCAO-induced WMLs. The findings were confirmed by Luxol fast blue (LFB) stain, which is designed for staining myelin/myelinated axons. We further found that pretreatment of metformin, rapamycin, or NMN reduced microglial activation and the number of M1 microglia, but increased the number of M2 microglia compared to the vehicle group. Importantly, the number of MBP+/Iba1+/CD68+ microglia was significantly reduced in the BCCAO rats pretreated with these three drugs compared with the vehicle group, suggesting that these drugs suppress microglial phagocytosis. No significant difference was found between the groups pretreated with metformin, rapamycin, or NMN. Our data suggest that metformin, rapamycin, or NMN could protect or attenuate cognitive impairment and WMLs by modifying microglial polarization and inhibiting phagocytosis. The findings may open a new avenue for VCI treatment.

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Section: Discussionmentioning

confidence: 99%

Metformin, Rapamycin, or Nicotinamide Mononucleotide Pretreatment Attenuate Cognitive Impairment After Cerebral Hypoperfusion by Inhibiting Microglial Phagocytosis

Zheng

Cheng

et al. 2022

Front. Neurol.

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“…Medical chemistry can also help find novel treatments by optimising formulations to improve some characteristics of the existing compounds. For example, this approach has been used to enhance the anti-parkinsonian efficacy of resveratrol ( Xiong et al, 2020 ), to increase the neuroprotective effect of metformin by the upregulation of autophagy ( Agostini et al, 2022 ) and to improve mitochondrial function ( Schlichtmann et al, 2021 ). Targeting the brain is still a challenge for any pharmacological approach.…”

Section: Discussionmentioning

confidence: 99%

Targeting Macroautophagy as a Therapeutic Opportunity to Treat Parkinson’s Disease

Sanchez-Mirasierra

Ghimire

Hernández-Díaz

et al. 2022

Front. Cell Dev. Biol.

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Macroautophagy, an evolutionary conserved catabolic process in the eukaryotic cell, regulates cellular homeostasis and plays a decisive role in self-engulfing proteins, protein aggregates, dysfunctional or damaged organelles, and invading pathogens. Growing evidence from in vivo and in vitro models shows that autophagy dysfunction plays decisive role in the pathogenesis of various neurodegenerative diseases, including Parkinson’s disease (PD). PD is an incurable and second most common neurodegenerative disease characterised by neurological and motor dysfunction accompanied of non-motor symptoms that can also reduce the life quality of patients. Despite the investment in research, the aetiology of the disease is still unknown and the therapies available are aimed mostly at ameliorating motor symptoms. Hence, therapeutics regulating the autophagy pathway might play an important role controlling the disease progression, reducing neuronal loss and even ameliorating non-motor symptoms. In this review, we highlight potential therapeutic opportunities involved in different targeting options like an initiation of autophagy, Leucine-rich repeat kinase 2 (LRRK2) inhibition, mitophagy, lysosomes, lipid metabolism, immune system, gene expression, biomarkers, and also non-pharmacological interventions. Thus, strategies to identify therapeutics targeting the pathways modulating autophagy might hold a future for therapy development against PD.

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“…Drug repositioning has become a strategy to reduce time and costs, proposing new applications for known drugs. This strategy was recently applied to identify treatments for several diseases such as tumors ( Aydin et al, 2022 ; Persico et al, 2022 ; Petrosyan et al, 2022 ), cardiac diseases ( Rouhana et al, 2021 ), and neurodegenerative diseases ( Bhat et al, 2020 ; Agostini et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study

Antoniciello

Roncarati

Zannoni

et al. 2022

Front. Mol. Biosci.

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Antibiotic-resistant bacterial pathogens are a very challenging problem nowadays. Helicobacter pylori is one of the most widespread and successful human pathogens since it colonizes half of the world population causing chronic and atrophic gastritis, peptic ulcer, mucosa-associated lymphoid tissue-lymphoma, and even gastric adenocarcinoma. Moreover, it displays resistance to numerous antibiotics. One of the H. pylori pivotal transcription factors, HP1043, plays a fundamental role in regulating essential cellular processes. Like other bacterial transcription factors, HP1043 does not display a eukaryote homolog. These characteristics make HP1043 a promising candidate to develop novel antibacterial strategies. Drug repositioning is a relatively recent strategy employed in drug development; testing approved drugs on new targets considerably reduces the time and cost of this process. The combined computational and in vitro approach further reduces the number of compounds to be tested in vivo. Our aim was to identify a subset of known drugs able to prevent HP1043 binding to DNA promoters. This result was reached through evaluation by molecular docking the binding capacity of about 14,350 molecules on the HP1043 dimer in both conformations, bound and unbound to the DNA. Employing an ad hoc pipeline including MMGBSA molecular dynamics, a selection of seven drugs was obtained. These were tested in vitro by electrophoretic mobility shift assay to evaluate the HP1043–DNA interaction. Among these, three returned promising results showing an appreciable reduction of the DNA-binding activity of HP1043. Overall, we applied a computational methodology coupled with experimental validation of the results to screen a large number of known drugs on one of the H. pylori essential transcription factors. This methodology allowed a rapid reduction of the number of drugs to be tested, and the drug repositioning approach considerably reduced the drug design costs. Identified drugs do not belong to the same pharmaceutical category and, by computational analysis, bound different cavities, but all display a reduction of HP1043 binding activity on the DNA.

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Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges

Cited by 43 publications

References 97 publications

Metformin, Rapamycin, or Nicotinamide Mononucleotide Pretreatment Attenuate Cognitive Impairment After Cerebral Hypoperfusion by Inhibiting Microglial Phagocytosis

Metformin, Rapamycin, or Nicotinamide Mononucleotide Pretreatment Attenuate Cognitive Impairment After Cerebral Hypoperfusion by Inhibiting Microglial Phagocytosis

Targeting Macroautophagy as a Therapeutic Opportunity to Treat Parkinson’s Disease

Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study

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