Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder pathologically distinguished by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Muscle rigidity, tremor, and bradykinesia are all clinical motor hallmarks of PD. Several pathways have been implicated in PD etiology, including mitochondrial dysfunction, impaired protein clearance, and neuroinflammation, but how these factors interact remains incompletely understood. Although many breakthroughs in PD therapy have been accomplished, there is currently no cure for PD, only trials to alleviate the related motor symptoms. To reduce or stop the clinical progression and mobility impairment, a disease-modifying approach that can directly target the etiology rather than offering symptomatic alleviation remains a major unmet clinical need in the management of PD. In this review, we briefly introduce current treatments and pathophysiology of PD. In addition, we address the novel innovative therapeutic targets for PD therapy, including α-synuclein, autophagy, neurodegeneration, neuroinflammation, and others. Several immunomodulatory approaches and stem cell research currently in clinical trials with PD patients are also discussed. Moreover, preclinical studies and clinical trials evaluating the efficacy of novel and repurposed therapeutic agents and their pragmatic applications with encouraging outcomes are summarized. Finally, molecular biomarkers under active investigation are presented as potentially valuable tools for early PD diagnosis.

Dual-Hit Model of Parkinson’s Disease: Impact of Dysbiosis on 6-Hydroxydopamine-Insulted Mice—Neuroprotective and Anti-Inflammatory Effects of Butyrate

“…Therefore, many PD experimental models have been extensively fine-tuned to recapitulate PD etiopathology and decipher the intricate connections among microbiota, gut, and brain [ 8 , 9 , 10 ], as well as discover new therapeutic tools to be efficaciously translated into clinical applications. Notably, to date, the most effective symptomatic treatment for Parkinson’s disease (PD) remains levodopa/carbidopa, although new emerging therapeutics and adjunctive nutraceuticals have been proposed [ 11 , 12 ]. The lack of full translation of experimental findings in PD patients has highlighted key drawbacks of simplified animal models in recapitulating the complex and degenerative human disease, opening an interesting scientific debate [ 13 ].…”

Omarigliptin Mitigates 6-Hydroxydopamine- or Rotenone-Induced Oxidative Toxicity in PC12 Cells by Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Actions

“…Neuroinflammatory processes have been associated with the pathogenesis of PD [ 56 , 57 ]. Moreover, evidence supports that controlling inflammatory processes can be exploited as promising interventional targets for PD and other neurodegenerative diseases, such as AD [ 58 ]. Therefore, we investigated the anti-inflammatory power of OMG in 6-OHDA- and rotenone-induced inflammatory processes.…”

Genetic and pharmacological reduction of CDK14 mitigates α-synuclein pathology in human neurons and in rodent models of Parkinson’s disease

“…One aspect of α-Syn pathology that has been difficult to overcome is the notion that different states of its post-translational modification or aggregation differentially affect disease pathogenesis: a clear image has yet to emerge as to the real culprit of α-Syn toxicity. Although novel strategies such as anti-sense oligonucleotides, immunotherapy and small molecule inhibitors of α-Syn aggregation are being explored ( 40 ), finding a target that can be pharmacologically inhibited still holds potential as a minimally invasive and simple strategy to lower α-Syn levels – especially when such treatment course would be made over several decades. Indeed, a growing body of evidence suggests that α-Syn may play a role not only at the presynaptic space, but also in the immune system ( 41–43 ).…”