Simultaneous application of two neurotrophic factors after spinal cord injury.

We have studied the application of voltage gradients to injured spinal cord which enhanced regeneration of axons and reduced their retrograde degeneration after injury. This led to an implanted electronic device producing electrical fields sufficient to induce regeneration in both ascending and descending tracts of white matter (called oscillating field stimulation [OFS]), which has been associated with behavioral recovery in animal models of spinal cord injury (SCI). OFS has also proven to benefit neurologically complete spinal cord injured dogs and humans in clinical trials. These studies, however, have failed to confirm benefit if applied after the sub-acute period of SCI. Here we report on combining OFS with the application of a non-toxic neurotrophic factor, inosine, using a behavioral model for "chronic" SCI, the cutaneous trunci muscle (CTM) reflex in adult guinea pigs. Inosine was delivered subcutaneously in guinea pigs for 28 days using implantable "osmotic pumps"--alone or in combination with OFS. In all animals, experimental and control treatments were withheld for three months after a right lateral hemisection of the thoracic spinal cord. Both inosine and the combination therapy produced a statistically significant recovery of CTM receptive fields silenced permanently by spinal cord hemisection in controls--though the combination therapy enhanced the time of the appearance of recovered regions of skin. Retransection of the cord in three recovered animals eliminated the CTM recovery confirming changes in neural connections were restricted to the cord and not due to changes in cutaneous peripheral innervation. Morphometry of anterogradely labeled white matter revealed a statistically enhanced regeneration of ascending and descending projections in animals treated with the combination "therapy" compared to inosine alone. These data suggest that combining neurotrophic factors of differing modes of action likely enhance the outcome from "chronic" SCI.