Researchers in the Department of Neurology at UCLA have identified pharmacologic compounds capable of crossing the blood brain barrier that dramatically promote neurite outgrowth after stroke, thereby promoting recovery.
Background: A stroke occurs when the blood supply of oxygen is interrupted to the brain, preventing brain tissue from receiving oxygen and nutrients: leading to brain cell death within minutes. It is estimated that every 40 seconds, someone in the United States will experience a stroke. There are over 7 million stroke survivors in the United States, though many have long-term disabilities. While early action can reduce brain damage and other complications, there are currently no drugs to promote recovery after stroke. Due to the often-devastating nature of the disability that follows stroke and its psychological and economic impact on patients, there is an urgent need to develop therapeutics to target patients during the recovery phase after stroke. Such agents will need the ability to traverse the blood brain barrier and promote the survival of stroke affected brain cells.
Innovation: Jason Hinman and colleagues in the Department of Neurology at UCLA have identified pharmacologic compounds that can promote a shift of neurons into a regenerative state. Using a mouse model that is resistant to neuronal injury, they identified patterns of gene expression in stroke-resistant neurons. This genetic database was then used to identify 2428 compounds with potential to mimic this transcriptional signature of stroke-resistance. These compounds were screened for candidates that could cross the blood-brain barrier, and efficacy of top hits was assessed using cultured cortical neurons from mouse brain and iPSC derived neurons. Researchers identified a significant number of compounds that could promote neurite and axon outgrowth, and further characterized a novel epigenetic mechanism by which these compounds exert their effect.
Importantly, these compounds have been shown to have the ability to cross the blood brain barrier, increasing their potential for use in promoting recovery after stroke. The genetic database that seeded the drug discovery, the identified epigenic mechanisms of action, and identified compounds themselves are thus promising candidates to target neuronal survival after stroke with high efficacy.
Applications: • Stroke Recovery • Neuronal Survival • Diagnostics • Therapeutics • Genetic Database
Advantages: • No current drug to promote recovery • Provides a database and a list of therapeutic drugs • Drugs promoting neuronal survival can be potentially utilized for diseases affecting neurodegeneration
State of Development: Researchers used a genetic knockout mouse model that is resistant to neuronal injury to develop a genetic characterization of injury-resistant neurons. This genetic database was then used to identify compounds that could cross the blood brain barrier, and in vitro experiments assessing neurite outgrowth and neuronal survival using top drug compounds were conducted to identify top candidates and their mechanism of action.
Related Papers (from the inventors only): Wang JT, Toh B, An J, Komuro Y, Godoy MI, Putman J, Carmichael ST, Damoiseaux R, Hinman JD. Loss of Sarm1 Mitigates Axonal Degeneration and Promotes Neuronal Repair After Ischemic Stroke. bioRxiv [Preprint]. 2025 Feb 25:2025.02.20.639171. doi: 10.1101/2025.02.20.639171. PMID: 40060510; PMCID: PMC11888178.
Keywords: Stroke, Blood-brain barrier, Drug Delivery, CNS, therapeutics, neuronal injury, in vitro screening, epigenetics