Intrathecal treatment with anti-Nogo-A antibody improves functional recovery in adult rats after stroke
- 509 Downloads
Stroke often results in devastating neurological disabilities with no specific treatment available to improve functional recovery. Neurite growth inhibitory proteins such as Nogo-A play a critical role in impeding regain of function after stroke. We have reported that treatment with anti-Nogo-A antibody using the intracerebroventricular route resulted in improvement of function and neuroplasticity in adult or aged rats after stroke. This present study tested a more clinically accessible route for applying anti-Nogo-A antibodies, the intrathecal route. Anti-Nogo-A or control antibody was administered intrathecally at lower lumbar levels 1 week after middle cerebral artery occlusion in adult rats. Our results show that anti-Nogo-A antibody delivered by this intrathecal route for 2 weeks penetrated into brain parenchyma and bound to myelin-enriched structures such as the corpus callosum and striatal white matter. Animals receiving anti-Nogo-A antibody treatment significantly improved recovery of function on the skilled forelimb reaching task as compared to stroke only and stroke/control antibody animals. These findings show that anti-Nogo-A antibody delivered through the intrathecal route is as effective in restoring lost functions after stroke as the intracerebroventricular route. This is of great importance for the future application of anti-Nogo-A immunotherapy for ischemic stroke treatment.
KeywordsIschemic Stroke Middle Cerebral Artery Occlusion Perivascular Space Prefer Limb Intrathecal Route
Supported by the Department of Veterans Affairs, MREP, NIH (Grant NS40960), Neuroscience Institute and Falk Foundation, Novartis Pharmatheuticals, and the Swiss NSF. We thank Dr. Chung-Sung Sung (VGH Taipei, Taiwan) for assisting in intrathecal catheterization, and Sam and Josh Rosales for their technical assistance.
- Kawamata T, Speliotes EK, Finklestein SP (1997) The role of polypeptide growth factors in recovery from stroke. In: Freund HJ, Sabel BA, Witte OW (eds) Brain plasticity. Lippincott-Raven, Philadelphia, pp 377–382Google Scholar
- Mackay J, Mensah GA (2005) The atlas of heart disease and stroke. In: World Health Organization and United Stated Center of Disease Control and Prevention, p 50Google Scholar
- Rennels ML, Gregory TF, Blaumanis OR, Fujimoto K, Grady PA (1985) Evidence for a ‘paravascular’ fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res 326:47–63PubMedCrossRefGoogle Scholar
- Schweigreiter R, Walmsley AR, Niederost B, Zimmermann DR, Oertle T, Casademunt E, Frentzel S, Dechant G, Mir A, Bandtlow CE (2004) Versican V2 and the central inhibitory domain of Nogo-A inhibit neurite growth via p75NTR/NgR-independent pathways that converge at RhoA. Mol Cell Neurosci 27:163–174PubMedCrossRefGoogle Scholar
- Seymour AB, Andrews EM, Tsai SY, Markus TM, Bollnow MR, Brenneman MM, O’Brien T E, Castro AJ, Schwab ME, Kartje GL (2005) Delayed treatment with monoclonal antibody IN-1 1 week after stroke results in recovery of function and corticorubral plasticity in adult rats. J Cereb Blood Flow Metab 25(10):1366–1375PubMedCrossRefGoogle Scholar
- Whishaw IQ (2005) Prehension. In: Whishaw IQ, Kolb B (eds) The behavior of the laboratory rat: a handbook with tests. Oxford University Press Inc., New York, pp 162–170Google Scholar
- Wiessner C, Bareyre FM, Allegrini PR, Mir AK, Frentzel S, Zurini M, Schnell L, Oertle T, Schwab ME (2003) Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats. J Cereb Blood Flow Metab 23:154–165PubMedCrossRefGoogle Scholar