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

The precursor nerve growth factor (ProNGF) and its receptor p75 neurotrophin receptor (p75 ^NTR ) are upregulated in several brain diseases, including ischemic stroke. The activation of p75 ^NTR is associated with neuronal apoptosis and inflammation. Thus, we hypothesized that p75 ^NTR 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 ^NTR , 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 ^NTR heterozygous knockout (p75 ^NTR+/- ) 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 ^NTR reduce infarction size, edema, and hemorrhagic transformation following ischemic stroke. Additionally, p75 ^NTR 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 ^NTR in ischemic stroke and modulation of p75 ^NTR 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.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)