O2066: Targeting p75NTR for Rescue of Cholinergic Neurons after Neonatal Hypoxic-Ischemia

Background: Memory and executive function are affected in child survivors of hypoxic-ischemic encephalopathy despite therapeutic hypothermia. Basal forebrain cholinergic systems are important in the control of these functions and are damaged after neonatal hypoxic-ischemia (HI). p75 neurotrophin receptor (p75NTR) is a tumor necrosis factor family member receptor expressed in adult cholinergic basal forebrain (cBF) neurons and modulate their survival. LM11-31 is an orally bioavailable small molecule p75NTR ligand with neuroprotective effects in mouse models of adult acute stroke and neurodegenerative diseases. Aim of this research is to determine if LM11A-31 as a late treatment rescues cBF neurons improving memory and executive function in survivors of neonatal HI in a mouse model.

Methods: C57BL6 mice were injured using the Rice-Vannucci HI model modified for mouse at postnatal day 10 (P10), with anesthesia exposed littermates serving as sham controls. LM11A-31 (in sterile water) or vehicle (sterile water) was administered intranasally (IN, at 50 mg/kg/day, 5 days/week) from P14-P60. Mice were killed at P270 following completion of touchscreen (TS) behavioral testing. Immunohistochemistry (IHC) for choline acetyltransferase (ChAT) was used to assess cBF neurons after treatments. All analysis were blinded to treatment, sex and time.

Results: While the number of ChAT + neurons in sublenticular regions of HI Veh mice were decreased at P270 (p=0.02 vs. sham, n=6-7 per group), LM11A-31 attenuated this loss (p= 0.04 HI drug vs. HI veh) with numbers similar to those documented in sham. Similarly, lower number of ChAT + neurons were documented in HI veh in nucleus basalis of Meynert (NBM, p=0.01 vs. sham), whereas these numbers were similar among sham and HI drug. LM11A-31 did not have an effect on the soma size of ChAT + neurons in NMB with both HI groups having smaller soma areas (p=0.01 vs. sham). Mean dendrite length and area in HI veh was decreased compared to HI drug (p=0.04) and sham (p=0.04). LM11A-31 also attenuated the effect of HI in Visual Discrimination (VD) and Reversal Learning (RL) testing with HI veh group needing more sessions to pass in VD and RL (p < 0.001 vs. sham), will HI drug group performed similar to sham.

Conclusion: Late LM11A-31 treatment after HI preserved number of cholinergic neurons in NBM and sublenticular regions of cBF, and preserved dendrite length and area in the NBM. LM11A-31 also improved the performance after HI in VD and RL, suggestive of improved attention, memory, learning, cognitive flexibility and executive function.