Rescue and regeneration of injured peripheral nerve axons by intrathecal insulin

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Neuroscience. 2006;139(2):429-49. Epub 2006 Mar 9.

Rescue and regeneration of injured peripheral nerve axons by

intrathecal insulin.

Toth C, Brussee V, ez JA, Mc D, Cunningham FA, Zochodne

DW.

Department of Clinical Neurosciences and the Hotchkiss Brain

Institute, University of Calgary, Room 168, 3330 Hospital Drive, NW,

Calgary, Alberta, Canada T2N 4N1.

Insulin peptide, acting through tyrosine kinase receptor pathways,

contributes to nerve development or repair. In this work, we examined

the direction, impact and repertoire of insulin signaling in vivo

during peripheral nerve regeneration in rats. First, we demonstrated

that insulin receptor is expressed on lumbar dorsal root ganglia

neuronal perikarya using immunohistochemistry. Immunoblots and

polymerase chain reactions confirmed the presence of both alpha and

beta insulin receptor subunits in dorsal root ganglia. In vivo and in

vitro assessment of dorsal root ganglion neurons showed preferential

localization of insulin receptor to perikaryal sites. In vivo,

intrathecal delivery of fluorescein isothiocyanate-labeled insulin

identified localization around dorsal root ganglia neurons.

The direction and impact of potential insulin signaling was evaluated

by concurrently delivering insulin or carrier over a 2 week period

using mini-osmotic pumps, either intrathecally, near nerve, or with

both deliveries, following a selective sural nerve crush injury. Only

intrathecal insulin increased the number and maturity of regenerating

sensory sural nerve axons distal to the crush site. As well, only

intrathecal insulin rescued retrograde loss of sural axons after

crush.

In a separate experiment, insulin also rescued retrograde loss and

atrophy of deep peroneal, largely motor, axons post-injury.

Intrathecal insulin increased the expression of calcitonin-gene-

related peptide in regenerating sprouts, increased the number of

visualized regenerating fiber clusters, and reduced downregulation of

calcitonin-gene-related peptide in dorsal root ganglia neurons.

Insulin delivered intrathecally does not appear to influence

expression of insulin-like growth factor-1 at dorsal root ganglion

neurons or near peripheral nerve injury, but was associated with

upregulation of insulin receptor alpha subunit in dorsal root

ganglia.

Intrathecal insulin delivery was associated with greater recovery of

thermal sensation and longer distances to stimulus response with the

pinch test following sural nerve crush.

Insulin signaling at neuron perikarya can drive distal sensory axon

regrowth, rescue retrograde alterations of axons and alter axon

peptide expression. Moreover, such actions are associated with

upregulation of its own receptor.