# RAGE Axis in the Pathogenesis and Treatment of CNS Neurodegeneration in Long-Term Hyperglycemia

## TL;DR

This review explores how the RAGE axis contributes to brain and spinal cord damage in diabetes and highlights its potential as a target for new treatments.

## Contribution

The paper provides a detailed analysis of the RAGE signaling axis in diabetes-related CNS neurodegeneration and its therapeutic potential.

## Key findings

- Long-term hyperglycemia increases oxidative stress and neuroinflammation in the CNS.
- RAGE signaling plays a key role in diabetic neurodegeneration and vascular complications.
- Targeting the RAGE axis may offer novel biomarkers and therapies for diabetes-related CNS damage.

## Abstract

Diabetes mellitus is one of the fastest-growing non-communicable diseases worldwide. The increasing global prevalence of diabetes has been accompanied by a corresponding rise in the incidence of diabetic micro- and macrovascular complications and related dysfunctions in the central nervous system. Studies demonstrated that patients with diabetes are more susceptible to cognitive impairment due to the diminished ability of neuronal cells to protect against increased production of reactive oxygen species and activated neuroinflammatory pathways. In the spinal cord, long-term hyperglycemia leads to neuronal dysfunction due to increased activation of glial cells and neuroinflammation and elevated oxidative stress, triggering micro- and macrovascular changes and leading to the development of peripheral nerve dysfunctions and neuropathies. Despite extensive efforts, however, the precise molecular mechanisms underlying the pathogenesis of diabetic complications have yet to be fully uncovered, proving to be a major hurdle in designing therapies to stop the progress of diabetes-triggered susceptible tissue and organ deterioration in affected subjects. In this review, we discuss in detail the role of the receptor for advanced glycation end-products (RAGE) and its major signaling partners in the development of CNS neurodegenerative changes in diabetes and the potential for novel biomarkers and treatments using targeting RAGE signaling axis.