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Role of Advanced Glycation Endproducts on Neuronal Degeneration and their Contribution to the Development of Peripheral Neuropathy

Grant number: 22/08417-7
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): December 01, 2022
Effective date (End): May 31, 2026
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Vanessa Olzon Zambelli
Grantee:Gessica Sabrina de Assis Silva
Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Advanced Glycation End Products (AGEs) are formed from the irreversible binding of sugar molecules with proteins such as collagen. Studies show that the formation of AGEs is associated with the development of peripheral neuropathy and pain. Our group previously demonstrated that sensory neurons gain pro-nociceptive function when in the presence of AGEs. Despite this evidence, we do not yet know the mechanisms by which AGEs contribute to neuronal hypersensitization, as well as to the axonal degeneration responsible for peripheral neuropathy. Thus, the objective of this work is to evaluate the role of AGEs in the neural degeneration processes involved in hypernociception. Therefore, we will initially characterize in sensory neurons the participation of AGEs on (a) activation of pro-nociceptive signaling pathways (MAPKs, ATF3, PI3K/Akt); (b) cell death pathways (BAX and BCL2); (c) on neuronal mitochondrial function, such as ROS production, H2O2 and mitochondrial membrane potential; (d) on neuronal sensitivity to calcium. Assays will be conducted in the presence or absence of AGE receptor antagonists (RAGES). Finally, we will evaluate the effect of AGEs on axonal degeneration in an ex vivo mouse peripheral nerve explant model. Therefore, we will evaluate (a) cytoskeleton dynamics; (b) axonal and myelin basic protein expression and integrity; (c) beyond the dynamics of Wallerian degeneration and neural regeneration. This work may contribute to the establishment of a new study platform for neurodegenerative diseases, as well as contribute to the understanding of the role of AGEs in this process.

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