A Novel BDNF Potentiator for the Treatment of Neonatal Brain Injury

Perinatal brain injury resulting in intellectual impairment and cerebral palsy affects more than 10,000 infants each year in the United States (1 to 3 per 1000 births). There is no therapy other than supportive care to prevent brain damage in hypoxic-ischemic (HI) encephalopathy (HIE) in premature infants. Due to the complex nature of the pathophysiological events, single-mechanism drug interventions in clinical studies have failed, and there remains an unmet medical need for therapeutics that prevent secondary neuronal damage. Brain-derived neurotrophic factor (BDNF) through activation of its high affinity receptor, TrkB, is a key player in promoting learning, and therapeutic strategies to enhance BDNF signaling protect against HI- induced injury. Treatment with systemic BDNF is limited by its short plasma half-life and poor brain penetration. Our research has circumvented these limitations through the development of cyclized-peptides targeting PSD-95, a TrkB associated synaptic scaffolding protein required for BDNF-induced signaling. We developed a macrocyclic compound, Syn3, that specifically binds the PDZ3 domain of PSD-95. Syn3 increases the recruitment of PSD-95 to TrkB to augment prosurvival signaling. Attached to the macrocycle is a cell–penetrating C-R(7) moiety that further mediates neuroprotection by reducing mitochondrial membrane hyperpolarization and the generation of reactive oxygen species. In a series of preclinical studies in a HI rodent model we found that Syn3 rapidly penetrates the CNS to reduce the degree of injury. The overall goal is to investigate the efficacy of our newly defined neuroprotective and immunomodulatory peptidomimetic, Syn3, to attenuate HI-related brain damage in the neonate. We hypothesize that administration of the optimal dose of Syn3 during the therapeutic time window will reduce brain injury, decrease neuronal and glial cell death, decrease apoptosis, free radical exposure and improve short and long-term behavioral outcomes. In Aim 1 we will determine the optimal dose and therapeutic time window for neuroprotection with Syn3 after HI related brain injury in the neonate. Aim 2 will assess the short and long-term neuroprotective efficacy of Syn3 administration after HI related brain injury on molecular (Aim 2.1) and behavioral (Aim 2.2) outcomes.