Elsevier

Neurobiology of Disease

Volume 37, Issue 2, February 2010, Pages 237-242
Neurobiology of Disease

Review
Translating the frontiers of brain repair to treatments: Starting not to break the rules

https://doi.org/10.1016/j.nbd.2009.09.005Get rights and content

Abstract

The field of neural repair in stroke has identified cellular systems of reorganization and possible molecular mechanisms. Conceptual barriers now limit the generation of clinically useful agents. First, it is not clear what the causal mechanisms of neural repair are in stroke. Second, adequate delivery systems for neural repair drugs need to be determined for candidate molecules. Third, ad hoc applications of existing pharmacological agents that enhance attention, mood or arousal to stroke have failed. New approaches that specifically harness the molecular systems of learning and memory provide a new avenue for stroke repair drugs. Fourth, combinatorial treatments for neural repair need to be considered for clinical therapies. Finally, neural repair therapies have as a goal altering brain connections, cognitive maps and active neural networks. These actions may trigger a unique set of “neural repair side effects” that need to be considered in planning clinical trials.

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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