Inosine Promotes Stroke Recovery
August 1, 2002 3 minutes read
Abstract & Commentary
Source: Chen P, et al. Inosine induces axonal rewiring and improves behavioral outcome after stroke. Proc Natl Acad Sci. 2002;99:9031-9036.
Despite recent advances, therapy for acute stroke remains minimal. Thrombolysis is hampered by damaging side effects and restrictive time windows. Neuroprotection has failed in every human trial despite promising animal data. Given these limits, the possibility of enhancing recovery through neuronal regeneration offers an enticing new avenue for stroke treatment.
In the present study, inosine, a naturally occurring purine nucleoside, was injected into the ventricular system of rats with experimentally induced right hemispheric strokes. Strokes were induced surgically. In the first study, conducted at Harvard, the middle cerebral artery (MCA) was occluded and inosine was injected into the cisterna magna. In the second, at the University of Lethbridge, Canada, both the MCA and the anterior cerebral arteries (ACA) were occluded with inosine injected into the lateral ventricle on the healthy side. Animals were studied behaviorally and histochemically.
Rats were tested for behaviors such as fore- and hindlimb placing or reaching for food. Treated animals performed significantly better than vehicle-treated rats on every modality. Remarkably, even when free to use either paw, treated animals used their paretic limb to retrieve food pellets. None of the vehicle-treated animals used their paretic limb to reach for food, even with their good limb constrained.
Infarct volumes showed no difference between treated and control patients, indicating that inosine had no neuroprotective effect. Any benefit of inosine, therefore, resulted from axonal reorganization rather than any reduction in the magnitude of the stroke itself. In histological studies, axons originating in the intact hemisphere were labeled with a tracer (BDA) that was transported to distal axon terminals. In both the corticorubral and corticospinal tracts, significantly increased axonal sprouting was observed into the damaged side. Treated animals showed increased levels of GAP-43—a marker of axonal growth not appreciably seen in controls. Inosine, acing through direct intracellular mechanisms, has been shown in cell culture to upregulate GAP-43 gene expression, and may thus do so in vivo as well.
Commentary
It is well appreciated that a limited degree of rewiring occurs after stroke. Recovery can be enhanced with physical therapy, in particular, with the "constraint-induced" paradigm where patients are forced to use the paretic limb. Inosine appears to significantly augment this process. Unfortunately, prior pharmacological attempts at stimulating stroke recovery have failed. Drugs such as the myelin constituent CDP-choline (Citocoline) and bFGF, a neuronal growth factor, have shown positive results in animals and preliminary human studies, but failed in Phase III trials.
The present data are, therefore, viewed with some trepidation. As Chen and colleagues note, it will be important to clarify practical issues such as the eligible time window for this therapy. Inosine was dosed immediately in these rats, but previous studies by Chen et al have indicated benefits up to 24 hours after stroke. Further, in contrast to rats with intraventricular catheters, human subjects will require alternative dosing routes, such as intravenous infusions, which will achieve much lower CNS levels. Fortunately, since inosine is a naturally occurring substance, it will likely be tolerated by humans in fairly high doses. This differentiates it from glutamate antagonists, antioxidants, and other previously studied neuroprotective drugs that have been severely limited by toxicity. —Alan Z. Segal
Dr. Segal, Assistant Professor, Department of Neurology, Weill-Cornell Medical College, Attending Neurologist, New York Presbyterian Hospital, is Assistant Editor of Neurology Alert.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content