Molecular mechanisms of developmental pathways in neurological disorders: a pharmacological and therapeutic review

Abstract

Developmental signalling pathways such as Wnt/β-catenin, Notch and Sonic hedgehog play a central role in nearly all the stages of neuronal development. The term ‘embryonic’ might appear to be a misnomer to several people because these pathways are functional during the early stages of embryonic development and adulthood, albeit to a certain degree. Therefore, any aberration in these pathways or their associated components may contribute towards a detrimental outcome in the form of neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and stroke. In the last decade, researchers have extensively studied these pathways to decipher disease-related interactions, which can be used as therapeutic targets to improve outcomes in patients with neurological abnormalities. However, a lot remains to be understood in this domain. Nevertheless, there is strong evidence supporting the fact that embryonic signalling is indeed a crucial mechanism as is manifested by its role in driving memory loss, motor impairments and many other processes after brain trauma. In this review, we explore the key roles of three embryonic pathways in modulating a range of homeostatic processes such as maintaining blood–brain barrier integrity, mitochondrial dynamics and neuroinflammation. In addition, we extensively investigated the effect of these pathways in driving the pathophysiology of a range of disorders such as Alzheimer's, Parkinson's and diabetic neuropathy. The concluding section of the review is dedicated to neurotherapeutics, wherein we identify and list a range of biological molecules and compounds that have shown enormous potential in improving prognosis in patients with these disorders.

Genome-Wide Gene-Set Analysis Identifies Molecular Mechanisms Associated with ALS

“…The Shh protein plays a critical role in the development processes in multi-cellular organisms through complex signaling cascades [ 52 ]. The Shh pathway has a key role in the cellular differentiation of multiple organs, in embryonic development, repair processes and especially in neuronal development [ 52 , 53 ]. Specifically, the Shh signaling pathway has been strongly associated, among others, with the development of the neural tube, motor neurons, the regulation of CNS polarity, neuronal regeneration and proliferation, stem cell renewal, and patterning of the developing thalamus and ventral forebrain [ 52 , 53 , 54 ].…”

“…The Shh pathway has a key role in the cellular differentiation of multiple organs, in embryonic development, repair processes and especially in neuronal development [ 52 , 53 ]. Specifically, the Shh signaling pathway has been strongly associated, among others, with the development of the neural tube, motor neurons, the regulation of CNS polarity, neuronal regeneration and proliferation, stem cell renewal, and patterning of the developing thalamus and ventral forebrain [ 52 , 53 , 54 ]. Shh is also involved with proliferation-linked signaling cascades after binding to a receptor complex, including Ptc-1 and smoothed G-protein coupled receptor [ 24 , 25 ].…”

The mechanism of microglia-mediated immune inflammation in ischemic stroke and the role of natural botanical components in regulating microglia: A review

“…In addition, NF-κB regulates the expression and activation of MMPs, leading to leakage of the BBB and exacerbating the inflammatory response ( 129 , 130 ). (2) Notch signaling: Notch signaling in response to LPS activation enhances IFN-γ production by co-recruiting p50 and c-Rel ( 131 , 132 ). Notch signaling exacerbates ischemic brain injury by prolonging NF-κB activation with concomitant persistent inflammation and enhancing microglia/macrophage-induced neurotoxicity ( 131 , 133 ).…”

Developmental pathways linked to the vulnerability of adult midbrain dopaminergic neurons to neurodegeneration

“…Only those secreted signaling factors and nuclear transcription factors (TFs) active in the mDA domain during prenatal/embryonic development and additionally during adulthood are considered as “developmental factors.” The usability of these factors for preventive or therapeutic interventions in the PD brain is also reviewed, but the myriad of in vitro studies in this regard are not addressed here. The involvement of these signaling and/or transcriptional cascades in ongoing neurodegenerative processes associated with PD are not discussed as they were recently reviewed by others ( Jha et al, 2022 ). This article does not delve into the mDA ontogenic and PD-associated programmed cell death (apoptosis; Burke, 2004 ; Savitt et al, 2005 ; Erekat, 2018 ; Robinson et al, 2018 ) or the role of “classical” neurotrophic factors, such as glial cell derived neurotrophic factor (GDNF), brain derived neurotrophic factor (BDNF), cerebral dopamine neurotrophic factor and mesencephalic astrocyte derived neurotrophic factor ( Chmielarz and Saarma, 2020 ), in this context.…”