Cortical PKC Inhibition Promotes Axonal Regeneration of the Corticospinal Tract and Forelimb Functional Recovery After Cervical Dorsal Spinal Hemisection in Adult Rats

Cerebral Cortex, 2014 · DOI: 10.1093/cercor/bht162 · Published: June 28, 2013

Spinal Cord Injury Regenerative Medicine Genetics

Simple Explanation

The study investigates whether delivering a PKC inhibitor (GÖ6976) directly to the corticospinal neurons can promote regeneration of the corticospinal tract (CST) and improve forelimb function after spinal cord injuries in rats. Cortical delivery of GÖ6976 reduced injury-induced activation of conventional PKCα and PKCβ1 in CST neurons, promoted regeneration of CST axons through and beyond a cervical DH at C4, formed new synapses on target neurons caudal to the injury, and enhanced forelimb functional recovery in adult rats. When combined with lenti-Chondroitinase ABC treatment, cortical administration of GÖ6976 promoted even greater CST axonal regeneration and recovery of forelimb function.

Study Duration

7 weeks

Participants

68 adult female SD rats (200–220 g)

Evidence Level

Not specified

Key Findings

1
Cortical delivery of GÖ6976 reduced injury-induced activation of conventional PKCα and PKCβ1 in CST neurons.
2
Cortical delivery of GÖ6976 promoted regeneration of CST axons through and beyond a cervical DH at C4 and formed new synapses on target neurons caudal to the injury.
3
Combined treatment with cortical delivery of GÖ6976 and intraspinal injection of lenti-ChABC signiﬁcantly enhanced CST axonal regeneration.

Research Summary

The study demonstrates that direct cortical delivery of the PKC inhibitor GÖ6976 promotes CST axonal regeneration and enhances forelimb functional recovery in rats with cervical spinal cord injuries. The effect is critically dependent on the efficient blockage of injury-induced PKC activation in the soma of layer V CST neurons. A combined strategy with cortical delivery of GÖ6976 and lesion site delivery of ChABC had a synergistic effect on promoting greater anatomical regeneration and functional recovery than when GÖ6976 was used alone.

Practical Implications

Novel Therapeutic Strategy

Cortical delivery of PKC inhibitors represents a novel approach for promoting axonal regeneration after spinal cord injury.

Combinatorial Therapy

Combining PKC inhibition with ChABC treatment enhances axonal regeneration and functional recovery, suggesting a promising therapeutic avenue.

Site-Specific Drug Delivery

The study highlights the importance of site-specific drug delivery, as cortical delivery of GÖ6976 was more effective than intrathecal or intraperitoneal administration.

Study Limitations

1
It remains unclear, however, why corticospinal neurons and sensory neurons respond differently to PKC inhibition.
2
GÖ6976 has been proﬁled against 300 kinases and other pathways besides PKCα and PKCβ1 may be involved in the effect.
3
The molecular weight of GÖ6976 is 378.4, which may allow it to pass freely through the blood–brain barrier following the intrathecal (IT) or intraperitoneal (IP) delivery.

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