About this Research Topic
Neurodegenerative disorders represent one of the most significant problems in basic and clinical medicine today. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are incurable, widespread, and the most common neurodegenerative pathologies. The current methods for AD and PD treatment are symptomatic, they do not halt the progression of the disease, nor ameliorate cognitive deficits. Major efforts are aimed at the discovery of a new effective pathogenesis-relevant therapy for AD and PD that would block the disease course and restore all the compromised functions.
AD and PD pathogenesis is largely associated with perturbations of the cellular proteostasis network responsible for the maintenance of protein homeostasis with the accumulation of neurotoxic protein aggregates in the brain, i.e. toxic forms of amyloid-beta, alpha-synuclein, and tau protein. It is believed that the imbalance between the neurotoxic protein production and removal contributes to their abnormal accumulation, and those mechanisms become impaired with aging and disease. Recent data show that impaired clearance plays an important role in the prevalent sporadic forms of AD and PD. Hence, modulating the rate of toxic protein elimination through enhancing the autophagy or expression of proteins involved in the metabolism of amyloid-beta or alpha-synuclein has attracted increasing attention.
However, neurodegenerative disorders have a multifactorial etiology and involve various pathological processes in addition to neurotoxicity of protein aggregates, such as oxidative stress, neuroinflammatory response, disturbed neurotrophic function and neurogenesis, synaptic and neurotransmission dysfunction, ion disbalance, etc. that often closely interact and overlap. Thus, multipurpose therapy aimed at various important pathogenetic hubs is a novel trend regarded as quite a promising strategy for AD and PD therapy.
Multipurpose or multi-target therapy including drug combinations aimed at various important pathogenetic hubs in the course of AD and PD is regarded currently as a relevant and promising approach. Several research teams around the world work within a CDMT strategy (combination-drugs-multi-targets). For instance, some studies have examined hybrids of tacrine and a chelating substance deferiprond and reported on the development of tacrine hybrids with dihydropyrimidines; recent studies also tested several multi-targeted polyphenol-based substances such as the properties of 3-aminomethylindoles and 7-azaindoles, which reduce the calcium load on neurons and activate phosphotase 2A, etc. Moreover, antibiotic drug ceftriaxone was found to produce neuroprotective effects both in AD and PD models through suppressing the glutamate-induced excitotoxicity, inhibition of alpha-synuclein polymerization, modulating the expression of genes related to amyloid-beta metabolism, and enhancing neurogenesis and recovery of neuronal density. Finally, recently promising results of clinical trials of GV-971 for treating people with mild to moderate Alzheimer’s disease have been reported. GV-971 inhibits the formation of amyloid-beta fibrils and neuroinflammation, and it reconditions the dysbiosis of gut microbiota.
This Research Topic is dedicated to collect novel experimental strategies and innovative combinatory approaches for the multipurpose treatment of AD and PD.
We welcome all types of articles providing input to this important research field through an in-depth analysis and novel experimental results from both in vivo and in vitro settings aiming to gain new insights from the experimental animal models and human studies. We expect articles mainly focused on the approaches of multipurpose therapy including multipotent drugs and substances or combinations aimed at two or more pathogenetic hubs involved in the AD or PD pathology such as:
· metabolism of pathological proteins, cellular proteostasis;
· neuroinflammation, disturbed neuro-immune interaction;
· dysbiosis of gut microbiota;
· oxidative stress, mitochondria dysfunction;
· neurotrophic dysfunction, disturbed neurogenesis;
· disturbed synaptic and neuronal plasticity, neurotransmission dysfunction;
· ion disbalance.
Keywords: Neurodegeneration, biomarkers, experimental therapy, animal models, drug development and repositioning
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