| Summary: | Traumatic injury to the central nervous system (CNS) results in neurological deficits, in part,
due to axonal regeneration failure. This is functionally exemplified in spinal cord injury by
motor and sensory paralysis. Regeneration failure has been attributed to several factors,
including intrinsic neuronal limitations to regeneration, as well as numerous inhibitory
molecules present in the injured CNS environment. The impact of intrinsic neuronal factors
is investigated here.
A transition from a permissive to a restrictive repair period exists in the developing chick
on approximately embryonic day (E) 13, possibly due to the formation of an extrinsic
inhibitory environment preventing axonal growth, and/or an intrinsic inability of mature
neurons to regenerate. By fluorescent labeling of brainstem-spinal neurons in ovo, I was able
to subsequently track the capacity of specific populations of young (E8) versus mature (El 7)
brainstem-spinal neurons to regrow neurites (i.e. presumptive axons) in vitro on permissive
growth substrates. When cultured on E8, robust neurite growth was observed from all
brainstem populations examined. In contrast, when cultured on El7, significant neurite
growth was seen only from raphe-spinal neurons. Thus, brainstem-spinal neurite regrowth
may dependent on both neuronal age and phenotype, suggesting that intrinsic neuronal
properties may contribute to axonal regeneration failure.
Because regeneration may depend on intrinsic neuronal properties, it may be beneficial to
pharmacologically enhance the axonal growth capacity of neurons. Injured neurons respond
characteristically (i.e. growth cone collapse or neurite retraction) to various molecules that
inhibit axonal growth, including myelin proteins and chondroitin sulfate proteoglycans
(CSPG). Accordingly, it is possible that intracellular signaling from several inhibitory
molecules converge onto a common regulatory pathway of axonal growth inhibition, i.e. the
Rho-GTPase. I tested in vitro whether pharmacological inhibition of a major downstream
effector of Rho, Rho-kinase (ROCK), promoted neurite outgrowth of dorsal root ganglia
(DRG) neurons grown on inhibitory substrates of aggrecan (a CSPG), myelin, and spinal
cord cryosections. Indeed, ROCK inhibition promoted neurite outgrowth several-fold, as well
as significantly altering the actin-based morphology of growth cones. The data support the
notion that suppression of Rho-pathway activity may be a viable therapeutic avenue for
enhancing axonal regeneration within the injured adult CNS.
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