Larry Benowitz, PhD

Stroke & Spinal Cord Regeneration

Functional recovery after stroke

Inosine rewires neural connections and improves performance after stroke. Stroke is the leading cause of disability among adults in the U.S. and the third leading cause of death. Several years ago, the Benowitz lab discovered that inosine, a small, naturally occurring molecule, stimulates neurons to extend nerve fibers (axons) in cell culture and promotes the rewiring of brain connections after stroke in mature animals. In a new study published this year, Dr. Zai and other members of the lab showed that in rats, inosine can help restore skilled movements with the limb affected by a stroke. At a molecular level, they found that inosine attenuates changes in gene expression associated with the loss of normal inputs in the neurons that form new connections, and induces the expression of genes related to forming axons and synapses. This work was carried out in collaboration with the labs of Leif Havton, Daniel Geschwind and Giovanni Coppola at UCLA, and forms the basis for studying the suitability of inosine for treating stroke patients.

In a collaborative study with Stephen Strittmatter of Yale, they found that combining inosine with NEP1-40, an agent that counteracts some of the signals in nerve cells' extracellular environment that normally suppress axon growth, causes more brain rewiring than either treatment alone and restores skilled use of the limb affected by the stroke back to normal.

Inosine enhances recovery from spinal cord injury. Spinal cord injury (SCI) most commonly affects people in the prime of life. Depending on the location and severity of injury, this can result in life-long impairments in movement, sensation, and autonomic functioning. Dr. Zai and other members of the Benowitz Lab found that inosine greatly improves performance after SCI in rats, both in general locomotion and on tests requiring cortical integration of sensory inputs and fine movements. At an anatomical level, inosine promoted the formation of new axon branches in the raphespinal pathway, which regulates limb co-ordination, and the corticospinal tract, which mediates voluntary control of fine movements. They also found that inosine was equally effective whether delivered directly into the brain's ventricular system or intravenously (i.v.).