Enhancing axon growth and functional recovery after cerebral ischemia (stroke)

Abnormal blood flow to one side of the brain (due to clots or bleeds) is called stroke and often causes disability in the opposite side of the body. Therapies need to work when given many hours after injury, because there is typically a delay to admission to hospital and diagnosis. Stroke primarily affects elderly people, yet few studies have examined potential therapies for stroke in an aged model system. Encouragingly, recent research shows that even aged brains and spinal cords have some capacity for adapting to stroke. There are, however, no restorative therapies for stroke.
We have previously shown that a drug, called chondroitinase ABC, can boost growth of injured nerve fibers and can restore function lost after spinal cord injury in adult rats. To date, the potential of chondroitinase ABC for promoting neural and functional recovery after stroke has not been examined. We propose investigating this here.
Our study aims to overcome stroke-induced disabilities in limb function by encouraging compensation by spared (uninjured) nerve fibers of the brain and spinal cord. To simulate stroke in elderly people, a small stroke will be induced in the brain of anaesthetised elderly rats. Post-operative analgesia will be given. Combination therapy will be initiated one week later. To boost growth of nerve fibers from the opposite (uninjured) side of the brain, chondroitinase ABC will be injected into regions in the brain and spinal cord. Rats will be housed in environments known to encourage rehabilitation of the injured forepaw. Other rats will be used as controls in order to determine the effect of each part of the combination therapy. Rats will be tested weekly to assess recovery in rats treated with the therapies. After five weeks, tract tracing will be performed to determine whether uninjured nerve fibres have responded to treatment. Two weeks later, rats will be terminally anaesthetised to provide tissue for analysis. We will seek evidence that the combination therapy induced changes in nerve fiber connections that might explain any behavioural improvements observed.
Results will be communicated to the general public after any publication embargo is lifted via press release sanctioned by our public relations department. We will also contact science reporters at national newspapers as well as magazines including New Scientist. I also participate in outreach to inner city schools, discussing risk factors for stroke, work involving responsible use of animals and potential therapies for stroke.

There is no fully restorative treatment for cerebral ischemia (stroke). Stroke primarily affects elderly people, yet relatively few studies have examined potential therapies for stroke in an aged model system. The aged central nervous system (CNS) is considered less capable of adaptive change than the young CNS, yet recent research supports the idea that even aged brains have potential for adaptation after injury. Environmental enrichment, cognitive challenge and locomotor rehabilitation can promote some recovery of function, but further advances are required. We have previously shown that CNS axon growth is restricted by the presence of growth inhibitory molecules including chondroitin sulphate. We have also shown that degradation of chondroitin sulphate using an enzyme (chondroitinase ABC) promotes axon regeneration and enhances functional recovery after penetrating injury to the brain or spinal cord. To date, the potential of chondroitinase ABC for promoting neural and functional recovery after stroke has not been examined.
The present study aims to enhance recovery of limb function in a model of unilateral focal cerebral ischemia (stroke) using aged rats by evaluating the effects of a delayed treatment intervention consisting of the enzyme (chondroitinase ABC), limb rehabilitation and environmental enrichment. A battery of behavioural tests and tract tracing will be used to assess recovery of limb function and axon growth, respectively.