Neuroprotection and Immunomodulation by Demeclocycline (DMC) and Its Doubly Reduced Derivative (DDMC) on Neuronal Survival and Glial Reactivity Following Neonatal Peripheral Axotomy

• Grant number: 25/13906-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2025
• End date: July 31, 2027
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Luciana Politti Cartarozzi
• Grantee: Gabrielli Sacheto
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 22/06609-6 - Glutamatergic signaling after rachimedullary trauma: role of glial cells in the inflammatory response and excitotoxicity, AP.GR

Abstract

Peripheral nervous system injuries during the neonatal period, such as sciatic nerve axotomy, lead to neuronal degeneration and permanent functional deficits, making this an important experimental model for evaluating neuroprotective therapies. During the first week of life, mammals exhibit high sensitivity to nerve injury, allowing for detailed analysis of neuronal death and regeneration. One of the main contributors to motoneuron death after neonatal axotomy is glutamatergic excitotoxicity, characterized by excessive glutamate release and dysregulated activation of NMDA and AMPA receptors, leading to intracellular calcium overload, mitochondrial dysfunction, and activation of pro-apoptotic pathways. This process is exacerbated in the neonatal period due to the immaturity of synaptic regulatory mechanisms and the high plasticity of the developing nervous system.Tetracyclines, such as demeclocycline (DMC), have shown neuroprotective effects, including anti-inflammatory and anti-apoptotic properties that may mitigate excitotoxicity. However, their prolonged use is limited by antibiotic activity and potential hepatotoxicity. The non-antibiotic derivative, doubly reduced demeclocycline (DDMC), retains neuroprotective properties with lower risks of toxicity and microbial resistance. In this context, the aim of this project is to investigate the neuroprotective and immunomodulatory effects of DMC and DDMC in neonatal rats subjected to sciatic nerve axotomy, with a particular focus on glutamatergic excitotoxicity as a central mechanism of injury. We will assess neuronal survival, glial response, retrograde morphological changes, and synaptic input density to spinal motoneurons using Nissl staining, immunohistochemistry, and electron microscopy. Results will be quantified using appropriate image analysis software and statistical methods. Altogether, we aim to support the development of new therapeutic strategies for traumatic neuropathies, with translational potential to reduce sequelae and improve patients' quality of life.