Anti-Nogo-A Antibody Therapy Improves Functional Outcome Following Traumatic Brain Injury

Abstract

Background Traumatic brain injury (TBI) can cause sensorimotor deficits, and recovery is slow and incomplete. There are no effective pharmacological treatments for recovery from TBI, but research indicates potential for anti-Nogo-A antibody (Ab) therapy. This Ab neutralizes Nogo-A, an endogenous transmembrane protein that inhibits neuronal plasticity and regeneration. Objective We hypothesized that anti-Nogo-A Ab treatment following TBI results in disinhibited axonal growth from the contralesional cortex, the establishment of new compensatory neuronal connections, and improved function. Methods We modeled TBI in rats using the controlled cortical impact method, resulting in focal brain damage and motor deficits like those observed in humans with a moderate cortical TBI. Rats were trained on the skilled forelimb reaching task and the horizontal ladder rung walking task. They were then given a TBI, targeting the caudal forelimb motor cortex, and randomly divided into 3 groups: TBI-only, TBI + Anti-Nogo-A Ab, and TBI + Control Ab. Testing resumed 3 days after TBI and continued for 8 weeks, when rats received an injection of the anterograde neuronal tracer, biotinylated dextran amine (BDA), into the corresponding area contralateral to the TBI. Results We observed significant improvement in rats that received anti-Nogo-A Ab treatment post-TBI compared to controls. Analysis of BDA-positive axons revealed that anti-Nogo-A Ab treatment resulted in cortico-rubral plasticity to the deafferented red nucleus. Conclusions. Anti-Nogo-A Ab treatment may improve functional recovery via neuronal plasticity to brain areas important for skilled movements, and this treatment shows promise to improve outcomes in humans who have suffered a TBI.

Neuritogenic glycosaminoglycan hydrogels promote functional recovery after severe traumatic brain injury

“…Tissue-engineered CS hydrogels have been demonstrated to promote neuroprotection, potentiate endogenous NSC renewal and mediate cellular and functional repair after sTBI [14,20,21]. Previous reports using rodent TBI models have suggested that the period between 4-5 weeks post-TBI constitutes a 'sub-acute' period after sTBI induction when animals first demonstrate sustained functional deficits [21][22][23]. Evidence also suggests that this timepoint is useful to determine treatment effects and differences between treated and untreated animal cohorts.…”