The P75 Neurotrophin Receptor Inhibitor, Lm11a-31, Ameliorates Acute Stroke Injury and Modulates Astrocytic Prongf Publisher Pubmed



Nasoohi S^{1, 2} ; Tayefeh Ghahremani P¹ ; Alehossein P^{1, 3} ; Elyasizadeh S^{1, 2} ; Baniardalan S¹ ; Ismael S⁴ ; Vatanpour H² ; Ahmadiani A¹ ; Ishrat T⁵ Show Affiliations
Source: Experimental Neurology Published:2023

Abstract

The precursor form of nerve growth factor (proNGF) is essential to maintain NGF survival signaling. ProNGF is also among endogenous ligands for p75 neurotrophin receptor (p75ntr). Mounting evidence implies that p75ntr signaling contributes to neural damage in ischemic stroke. The present study examines the therapeutic effect of the p75ntr modulator LM11A-31. Adult mice underwent transient distal middle cerebral artery occlusion (t-dMCAO) followed by LM11A-31 treatment (25 mg/kg, i.p., twice daily) either for 72 h post-injury (acute phase) or afterward till two weeks post-stroke (subacute phase). LM11A-31 reduced blood-brain barrier permeability, cerebral tissue injury, and sensorimotor function in the acute phase of stroke. Ischemic brain samples showed repressed proNGF/P75ntr signaling and Caspase 3 activation in LM11A-31 treated mice, where we observed less reactive microglia and IL-1β production. LM11A-31 (20–80 nM) also mitigated neural injury induced by oxygen-glucose deprivation (OGD) in sandwich co-cultures of primary cortical neurons (PCN) and astrocytes. This concurred with JNK/PARP downregulation and reduced caspase-3 cleavage in the PCNs and was associated with repressed proNGF generation in astrocytes. Further in vitro experiments indicated human proNGF suppresses the pro-inflammatory phenotype in microglial cultures, as determined by a sharp decline in HMGB-1 production and moderate arginase-1 upregulation. Despite significant protection in acute stroke, LM11A-31 treatment did not improve cortical atrophy and sensorimotor function in the subacute phase. Our findings provide preclinical evidence supporting LM11A-31 as a promising therapy for acute stroke injury. Further investigations may elucidate if reduced astrocytic proNGF, an endogenous reservoir of pro-neurotrophins, may restrict the therapeutic window. © 2022