ReviewTranslating the frontiers of brain repair to treatments: Starting not to break the rules
Section snippets
What is neural repair?
All stroke patients exhibit some degree of functional recovery. This process occurs in a matter of days on the acute stroke service, and continues most dramatically for the first month in upper and lower extremity motor function (Kreisel et al., 2007) and for up to a year in language and other cognitive modalities (Hier et al., 1983, Kauhanen et al., 2000). This recovery is not complete, leading to the tremendous long term personal and financial burdens of this disease (Carmichael, 2006;
Delivery issues: Translating identified molecular systems into human therapies
Several molecular systems appear to induce or block neural repair after stroke and other CNS injuries. The serine/threonine kinase Mst3b is induced by inosine and mediates axonal sprouting and behavioral recovery (Chen et al., 2002, Zai et al., 2009). NogoA blocks axonal sprouting, and interfering with Nogo function produces behavioral recovery after stroke (Papadopoulos et al., 2002, Lee et al., 2004, Zai et al., 2009). EPO and G-CSF interact with mechanisms of early cell death and neural
Learning and memory, peri-infarct cortex and pharmacological repair therapies
Neurorehabilitation employs learning rules to guide therapy, such as learned non-use, mass action, contextual interference and distributed practice (Dobkin, 2003, Krakauer, 2006). These therapies for brain injury induce a reorganization in brain mapping that closely parallels that seen with memory and learning paradigms: an initially diffuse network of brain areas is gradually funneled down with training into a core set of areas directly involved in the tasks (Kelly et al., 2006, Butefisch et
Combinatorial treatments
The active promotion of neural repair after stroke may necessitate combination therapies. Data from initial spinal cord injury studies and axonal sprouting studies in optic nerve and stroke injury models indicates that it is not enough to simply block an axonal growth inhibitory system, such as the NogoA system (Benowitz and Carmichael, 2010). Adult neurons fail to regenerate appreciably, even with a more permissive environment, because they are not in a “growth state”. The Benowitz lab has
Conclusion: What is a tolerable side effect profile in repairing the brain?
Assuming that specific CNS drug or stem cell delivery issues have been worked out, neural repair therapies in stroke will, by definition, activate brain plasticity in the context of injury and reorganization. For a neurologist, ischemic stroke is characterized almost entirely by negative clinical symptoms: loss of function in the damaged brain circuits. Compared with other forms of brain injury, there are few “positive” symptoms in stroke. For example, less than 10% of ischemic stroke patients
Acknowledgments
Dr. Carmichael has received support from NIH NS045729 and NS053957 and the Larry L Hillblom Foundation.
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