TrkB Receptor Activation Reduces Neuroinflammation and Thalamic Injury Following Stroke
Abstract number :
3.042
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2021
Submission ID :
1826213
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:53 AM
Authors :
Feng Gu, MD, PhD - Stanford University; Chen Song – Neurology & Neurological Sciences – Stanford University; Isabel Parada – Neurology & Neurological Sciences – Stanford University; Tao Yang – Neurology & Neurological Sciences – Stanford University; Frank Longo – Neurology & Neurological Sciences – Stanford University; David Prince – Neurology & Neurological Sciences – Stanford University
Rationale: Stroke is a significant cause of epilepsy, especially in the elderly. In addition to direct neocortical damage induced by a focal infarction, orthodromic and antidromic neuronal injury and degeneration occur in connected thalamic structures that could contribute to establishment of epileptogenic circuits. Activation of microglia contributes to inflammation-related neuronal damage through release of cytokines and formation of neurotoxic A1 astrocytes that are important contributors to neuroinflammation following brain damage and drive neuronal death in multiple neurodegenerative diseases. BDNF-TrkB signaling can inhibit microglia activation, leading to the hypothesis that TrkB activation with a small molecule partial agonist will reduce neuroinflammation, neuronal injury and cell death in thalamus secondary to cortical ischemic stroke.
Methods: A focal cortical photothrombotic stroke was induced in the right somatosensory cortex in anaesthetized SD rats (P22-23) by photo-stimulation after injections of Rose Bengal. Control rats received the same Rose Bengal injection without photo-stimulation. Rats were treated for 7 days beginning the day of stroke with ip injections of saline or PTX BD4-3 (BD), a small molecule partial agonist of the BDNF TrkB receptor that has been shown to achieve functional brain levels following peripheral administration. Immunohistochemistry was performed 2 days after the last BD treatment and confocal microscopy was used to evaluate the effects of BD on microglia, reactive astrocytes, and neuronal loss in the affected thalamic regions.
Results: 1) There was significant neuron loss in thalamic nRT, VPL, and VPM nuclei (nRT: 140 ± 4.52 vs 68.09 ± 4.35, p< 0.001; VPL+VPM: 38.86 ± 2.60 vs 13.08 ± 2.40, p< 0.001), accompanied by microgliosis, astrogliosis (GFAP-IR in VPL+VPM: 7.73 ± 1.27 vs 23.70 ± 1.50 pixels, p< 0.001), reactive neurotoxic A1 astrocytes, and upregulated TNFα; 2) BD compared to saline treatment decreased microgliosis, astrogliosis (GFAP-IR in VPL+VPM: 23.70 ± 1.50 vs 6.713 ± 0.58 pixels, p< 0,001), the number of A1 astrocytes (nRT: 42.89 ± 3.18 vs 10.25 ± 1.25, p< 0.001; VPL+VPM: 94.33 ± 10.03 vs 25.25 ± 8.14, p< 0.01), and the level of TNFα, as well as neuron loss (nRT: 68.09 ± 4.35 vs 110.7 ± 5.61, p< 0.001; VPL+VPM: 13.08 ± 2.40 vs 25.91 ± 1.84; p< 0.01) in the affected thalamic regions.
Basic Mechanisms