Inosine Enhances Axon Sprouting and Motor Recovery after Spinal Cord Injury

Abstract

Although corticospinal tract axons cannot regenerate long distances after spinal cord injury, they are able to sprout collateral branches rostral to an injury site that can help form compensatory circuits in cases of incomplete lesions. We show here that inosine enhances the formation of compensatory circuits after a dorsal hemisection of the thoracic spinal cord in mature rats and improves coordinated limb use. Inosine is a naturally occurring metabolite of adenosine that crosses the cell membrane and, in neurons, activates Mst3b, a protein kinase that is part of a signal transduction pathway that regulates axon outgrowth. Compared to saline-treated controls, rats with dorsal hemisections that were treated with inosine showed three times as many synaptic contacts between corticospinal tract collaterals and long propriospinal interneurons that project from the cervical cord to the lumbar level. Inosine-treated rats also showed stronger serotonergic reinnervation of the lumbar cord than saline-treated controls, and performed well above controls in both open-field testing and a horizontal ladder rung-walking test. Inosine was equally effective whether delivered intracranially or intravenously, and has been shown to be safe for other indications in humans. Thus, inosine might be a useful therapeutic for improving outcome after spinal cord injury.

Purines: forgotten mediators in traumatic brain injury

“…) and spinal cord injury (SCI) (Kim et al . ). Evidence that astrocytic Nrf2 pathway activation confers protection against neuronal cell death in TBI/SCI (Mao et al .…”

“…) and intracellular activation of the Mst3b signaling cascade (Kim et al . ). However, the metabolism of inosine to urate by way of peripheral xanthine oxidase could in theory generate deleterious oxidative stress via its hydrogen peroxide byproduct (Kelley et al .…”

Enhancing Nervous System Recovery through Neurobiologics, Neural Interface Training, and Neurorehabilitation

“…Growth associated protein 43 (GAP43), a neuronal growth cone marker, is also induced in peri-infarct cortex after stroke (Stroemer et al, 1995; Schaechter et al, 2006). The purine nucleoside inosine works through a direct intracellular mechanism to induce expression of genes associated with axonal growth (e.g., GAP43, L1, and α-1 tubulin) and has been shown to induce axonal reorganization and improve behavioral outcomes after spinal cord injury and stroke (Zai et al, 2009, 2011; Kim et al, 2013), as well as restore levels of GAP43 in the hippocampus in rats after stroke (Chen et al, 2002; de Lima et al, 2012b; Dachir et al, 2014). …”

Reinnervated nerves contribute to the secretion function and regeneration of denervated submandibular glands in rabbits

“…Reinnervation and regeneration can be observed in the central and peripheral nervous system . After injury, the reinnervation of denervated targets by regeneration of injured axons is one of the neural mechanisms that compensates for the functional deficits caused by nerve injuries in peripheral nerves .…”

“…Altogether, these data suggest that reinnervated nerves play an important role in recovering the secretion function of, and tissue regeneration in, denervated rabbit SMGs. Reinnervation and regeneration can be observed in the central and peripheral nervous system (23,24). After injury, the reinnervation of denervated targets by regeneration of injured axons is one of the neural mechanisms that compensates for the functional deficits caused by nerve injuries in peripheral nerves (25)(26)(27).…”