Genetic and Pharmacological Modulation of P75 Neurotrophin Receptor Attenuate Brain Damage After Ischemic Stroke in Mice

Authors

Golnoush Mirzahosseini, Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.
Saifudeen Ismael, Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, LA, 70112, New Orleans, USA.
Mohd Salman, Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA.
Santosh Kumar, Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, TN, 38163, Memphis, USA.
Tauheed Ishrat, Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA. tishrat@uthsc.edu.

Abstract

The precursor nerve growth factor (ProNGF) and its receptor p75 neurotrophin receptor (p75) are upregulated in several brain diseases, including ischemic stroke. The activation of p75 is associated with neuronal apoptosis and inflammation. Thus, we hypothesized that p75 modulation attenuates brain damage and improves functional outcomes after ischemic stroke. Two sets of experiments were performed. (1) Adult wild-type (WT) C57BL/6 J mice were subjected to intraluminal suture-middle cerebral artery occlusion (MCAO) to induce cerebral ischemia. Pharmacological inhibitor of p75, LM11A-31 (50 mg/kg), or normal saline was administered intraperitoneally (IP) 1 h post-MCAO, and animals survived for 24 h. (2) Adult p75 heterozygous knockout (p75) and WT were subjected to photothrombotic (pMCAO) to induce ischemic stroke, and the animals survived for 72 h. The sensory-motor function of animals was measured using Catwalk XT. The brain samples were collected to assess infarction volume, edema, hemorrhagic transformation, neuroinflammation, and signaling pathway at 24 and 72 h after the stroke. The findings described that pharmacological inhibition and genetic knocking down of p75 reduce infarction size, edema, and hemorrhagic transformation following ischemic stroke. Additionally, p75 modulation significantly decreased several anti-apoptosis markers and improved sensory motor function compared to the WT mice following ischemic stroke. Our observations exhibit that the involvement of p75 in ischemic stroke and modulation of p75 could improve the outcome of ischemic stroke by increasing cell survival and enhancing motor performance. LM11A-31 has the potential to be a promising therapeutic agent for ischemic stroke. However, more evidence is needed to illuminate the efficacy of LM11A-31 in ischemic stroke.

Publication Title

Molecular neurobiology

Recommended Citation

Mirzahosseini, G., Ismael, S., Salman, M., Kumar, S., & Ishrat, T. (2023). Genetic and Pharmacological Modulation of P75 Neurotrophin Receptor Attenuate Brain Damage After Ischemic Stroke in Mice. Molecular neurobiology https://doi.org/10.1007/s12035-023-03550-1