Patients Stratification Strategies to Optimize the Effectiveness of Scavenging Biogenic Aldehydes: Towards a Neuroprotective Approach for Parkinson's Disease

Abstract

Parkinson’s disease (PD) is a clinically heterogeneous disorder with a multi-factorial pathology. Various molecular mechanisms are involved in the pathogenesis of PD, converging to oxidative stress and proteinopathy. The accumulation of reactive aldehydes (i.e., the dopamine metabolite DOPAL, lipid-peroxidation products, and advanced glycation end-products) has been reported in PD patients’ brains. Aldehydes easily react with primary amines such as lysine residues, which are involved in several regulatory processes in cells. Therefore, aldehyde adducts lead to severe consequences, including neuronal proteostasis, mitochondrial dysfunction, and cell death. In this review, we analyzed the scavenging role of amines toward toxic aldehydes in the brain. Interestingly, small molecules like metformin, rasagiline, hydralazine are already clinically available and used in the therapy for PD and other diseases. Hence, we propose to reevaluate this class of drugs as a disease-modifiers for PD, and we suggest that improved analysis of their pharmacology and bioavailability in the brain, together with a more precise patients stratification, should be considered before planning future clinical trials.

Scavenging neurotoxic aldehydes using lysine carbon dots

“… 1 PD is characterized by a multifactorial pathology, and accumulation of reactive aldehydes is perceived as a major etiopathogenic factor. 2 The dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) has been identified as a prominent aldehyde species generated in PD by enzymatic degradation of dopamine. 3 Aldehydes usually react with amino groups of lysine residues, leading to covalent adducts, protein cross-linking and aggregation, thus compromising cellular homeostasis.…”

Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges

“…In this case, the ability of metformin to effectively act as a disease modifier might depend on an early intervention in the prodromal phases of PD, when the neurodegenerative process is not irreversibly advanced. Hence, the development of new criteria for patients’ stratification strategies should be a primary goal to identify those individuals who could benefit most from metformin therapy in the long run [ 42 ].…”

“…In this frame, the administration of aminoguanidine, an analog of metformin, reduced α-syn aggregation and promoted its clearance via autophagy in MGO-treated cells and rescued the motor impairment observed in MGO-treated flies overexpressing the human α-syn [ 41 ]. Hence, we recently speculated that metformin could provide a similar scavenging activity towards MGO by preventing the accumulation of α-syn neurotoxic aggregates, but this could be extended to other aldehydes of neuropathological relevance in PD, i.e., aldehydes derived from oxidative stress and lipid peroxidation (4-hydroxynonenal (4-HNE), malondialdehyde (MDA)) or aldehydic molecules that accumulate from altered monoamine catabolic pathways (3,4-dihydroxyphenylacetaldehyde, 3,4-dihydroxyphenylglycoaldehyde, 5-hydroxyindole-3-acetaldehyde) [ 42 ]. Accordingly, a recent paper investigated the neuroprotective effect of metformin in a PD mouse model based on rotenone-induced dopaminergic neuron death [ 25 ].…”

“…Metformin bioavailability has been determined to be around 40–60% [ 71 ] with a half-life of about 6.2 h in the plasma and an elimination half-life of 17.6 h [ 72 ]. The molecule does not encounter hepatic metabolism and it is eliminated mainly through the urinary tract in its unmodified form [ 42 ]. One of the still-unsolved aspects regards the concentration and accumulation of the drug in the brain after administration and how metformin reaches the brain tissue.…”

DOPAL initiates αSynuclein-mediated impaired proteostasis in neuronal projections leading to enhanced vulnerability in Parkinson’s disease

“…Only one recent work reported increased levels of "αSyn dopaminylation" in the plasma of PD patients 57 . In this frame, the implementation of genetic screenings and suitable biomarkers oriented to the identification of subjects with increased risk of pathological DOPAL accumulation would be crucial for the early diagnosis of PD 58 . Such novel patient stratification strategies would also lead to a reconsideration of MAO inhibitors as therapeutic approach which, in past studies, did not match the requisites of disease-modifiers for PD.…”