Inosine Augments the Effects of a Nogo Receptor Blocker and of Environmental Enrichment to Restore Skilled Forelimb Use after Stroke

Abstract

Stroke is the leading cause of disability in much of the world, with few treatment options available. Following unilateral stroke in rats, inosine, a naturally occurring purine nucleoside, stimulates the growth of projections from the undamaged hemisphere into denervated areas of the spinal cord and improves skilled use of the impaired forelimb. Inosine augments neurons’ intrinsic growth potential by activating Mst3b, a component of the signal-transduction pathway through which trophic factors regulate axon outgrowth. The present study investigated whether inosine would complement the effects of treatments that promote plasticity through other mechanisms. Following unilateral stroke in the rat forelimb motor area, inosine combined with NEP1-40, a Nogo receptor antagonist, doubled the number of axon branches extending from neurons in the intact hemisphere into the denervated side of the spinal cord compared to either treatment alone and restored rats’ level of skilled reaching using the impaired forepaw to preoperative levels. Similar functional improvements were seen when inosine was combined with environmental enrichment (EE). The latter effect was associated with changes in gene expression in layer 5 pyramidal neurons of the undamaged cortex well beyond those seen with inosine or EE alone. Inosine is now in clinical trials for other indications, making it an attractive candidate for the treatment of stroke patients.

Modulation of Neural Plasticity as a Basis for Stroke Rehabilitation

“…65 Inosine combined with a Nogo receptor blocker or with environmental enrichment augmented the effects of these 2 treatment modalities on the restoration of skilled forelimb use after stroke. 66 These results demonstrate that the combination of behavioral and pharmacological adjuvant therapies may have additive or even synergistic effect in promoting the recovery of function after stroke. A 2-year inosine treatment was safe and well-tolerated in multiple sclerosis patients.…”

A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke

“…The degree of axonal sprouting in these connections has been correlated with behavioral recovery and can be enhanced with Nogo blockade and inosine delivery (1,43), but it has not been possible to block sprouting selectively in these circuits and to determine definitively their role in recovery. We used the ephrin-A5 system to both induce and block axonal sprouting and a hydrogel delivery system to influence molecular signaling selectively within periinfarct cortex, and we then assessed the patterns of connections in motor cortex circuits using three different neuroanatomical tracers with three statistical analysis measures.…”

The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative

“…Blockade of Nogo receptor 1 (NgR1) but not Nogo receptor 2 (NgR2) promotes axonal sprouting after stroke [69]. NgR1 antagonists have been tested in many stroke models and found to be effective in promoting recovery [97,[111][112][113]. NgR2 binds myelin-associated glycoprotein (MAG) [114].…”

“…The data from preclinical studies of axonal sprouting would suggest that this will not be effective, and preclinical models show that it is only modestly successful in either preventing the initial dysfunction after stroke or producing limited behavioral recovery [116]. Other molecular pathways for axonal sprouting, either induced in peri-infarct neurons or contralateral neurons [98], indicate promising targets for neural repair such as ephrin-A5, GDF10, and the use of the small molecule inosine [36,69,98,113]. Cell therapies appear to stimulate local axonal sprouting by tissue immunohistochemical staining [117][118][119], and in some cases by more detailed direct demonstration of axonal connections [120].…”