Stroke is a devastating disorder that leads to neuronal death and neurologic disability. We have shown that the brain's inherent ability to form new neuronal connections and restore lost function after stroke can be enhanced by neutralizing the inhibitory nature of the adult CNS through antibody therapy that neutralizes the protein Nogo-A. We now plan to study the ability of anti-Nogo-A immunotherapy to enhance functional recovery and neuronal plasticity in the chronic stroke impaired rat. This is an exciting and novel area of research and may benefit many more patients who suffer with chronic neurologic disabilities, even those resulting from causes other than stroke. In addition, understanding changes in neuronal plasticity following anti-Nogo-A immunotherapy given at a chronic stage of stroke could lead to improved therapeutic approaches for future clinical use. Therefore, we hypothesize that anti-Nogo-A immunotherapy when given to chronic stroke-impaired aged rats will result in improved functional outcome and enhanced anatomical plasticity in brain regions important for recovery. We will test our hypothesis in the following specific aims:
Specific Aim #1 - Determine whether treatment with anti-Nogo-A immunotherapy results in behavioral recovery when given two months after ischemic stroke in the aged rat. We will use behavioral tests of sensorimotor and cognitive recovery in the aged animal and study long term outcomes in order to enhance the translation of these results to clinical use.
Specific Aim #2 - Determine whether treatment with anti-Nogo-A immunotherapy results in neuroanatomical plasticity when given two months after ischemic stroke in the aged rat.
This aim will employ neuroanatomical tract tracing and Golgi-Cox staining to examine axonal and dendritic plasticity in areas important for sensorimotor recovery.
Specific Aim #3 - Determine if movements in the stroke-impaired forelimb return to pre-stroke movement patterns or if other compensatory strategies occur after stroke and anti-Nogo-A immunotherapy in aged rats using kinematic analysis. The goals of the present proposal are to test if our novel immunotherapy improves functional recovery in the chronic stroke-impaired aged rat. The results of these studies will have a tremendous impact on the field of neurorehabilitation by changing the way we view chronic stroke, i.e. no longer will a deficit be thought of as """"""""stable"""""""" or """"""""fixed"""""""", and recovery will be possible even for the chronically impaired stroke victim.
The incidence of stroke more than doubles in each successive decade for people over 55 years of age. The increasing numbers of elderly patients in the VA population make research into the basic mechanisms of neuronal repair in the aging brain of prime importance to the VA patient care mission. Previous work from our laboratory has advanced the potential use of anti-Nogo-A immunotherapy by demonstrating improvements in functional outcomes using clinically relevant experimental designs. The results of studies in this proposal may lead to new therapeutic approaches to improve sensorimotor functional outcome in patients suffering from chronic neurologic disabilities, where the deficit is thought of as fixed or stable. Furthermore, if ths therapy proves to be effective in the chronic stroke model, it might also play an important role in the development of strategies to treat patients at the chronic stage of other brain lesions, such as traumatic brain injury.
|Braun, Robynne G; Andrews, Ellen M; Kartje, Gwendolyn L (2012) Kinematic analysis of motor recovery with human adult bone marrow-derived somatic cell therapy in a rat model of stroke. Neurorehabil Neural Repair 26:898-906|
|Sarkey, J P; Chu, M; McShane, M et al. (2011) Nogo-A knockdown inhibits hypoxia/reoxygenation-induced activation of mitochondrial-dependent apoptosis in cardiomyocytes. J Mol Cell Cardiol 50:1044-55|
|Tsai, Shih-Yen; Papadopoulos, Catherine M; Schwab, Martin E et al. (2011) Delayed anti-nogo-a therapy improves function after chronic stroke in adult rats. Stroke 42:186-90|
|Pradhan, A D; Case, A M; Farrer, R G et al. (2010) Dendritic spine alterations in neocortical pyramidal neurons following postnatal neuronal Nogo-A knockdown. Dev Neurosci 32:313-20|
|Beltran, Erik J; Papadopoulos, Catherine M; Tsai, Shih-Yen et al. (2010) Long-term motor improvement after stroke is enhanced by short-term treatment with the alpha-2 antagonist, atipamezole. Brain Res 1346:174-82|
|Papadopoulos, Catherine M; Tsai, Shih-Yen; Guillen, Veronica et al. (2009) Motor recovery and axonal plasticity with short-term amphetamine after stroke. Stroke 40:294-302|