Minocycline protects motor but not autonomic neurons after cauda equina injury

Abstract

Conus medullaris/cauda equina injuries typically result in loss of bladder, bowel, and sexual functions, partly as a consequence of autonomic and motor neuron death. To mimic these injuries, we previously developed a rodent lumbosacral ventral root avulsion (VRA) injury model, where both autonomic and motor neurons progressively die over several weeks. Here, we investigate whether minocycline, an antibiotic with putative neuroprotective effects, may rescue degenerating autonomic and motor neurons after VRA injury. Adult female rats underwent lumbosacral VRA injuries followed by a 2-week treatment with either minocycline or vehicle injected intraperitoneally. The sacral segment of the spinal cord was studied immunohistochemically using choline acetyltransferase (ChAT) and activated caspase-3 at 4 weeks post-operatively. Minocycline increased the survival of motoneurons but not preganglionic parasympathetic neurons (PPNs). Further investigations demonstrated that a larger proportion of motoneurons expressed activated caspase-3 compared to PPNs after VRA injury and indicated an association with minocycline's differential neuroprotective effect. Our findings suggest that minocycline may protect degenerating motoneurons and expand the therapeutic window of opportunity for surgical repair of proximal root lesions affecting spinal motoneurons.

Figure 1

Minocycline protects motoneurons but not PPNs from cell death at 4 weeks after VRA injury. S1 spinal cord sections from vehicle (a) or minocycline (b) groups were immunohistochemically processed for ChAT to quantify the percent of surviving PPNs and motoneurons. Minocycline administration resulted in a significant increase in motoneuron survival, but not PPN survival (* p<0.05; c). Note that significantly more PPNs survived than motoneurons after injury in the vehicle group. Scale bar = 60 µm and applies to all high magnification images.

Figure 2

Differential expression of activated caspase-3 between PPNs (a, c, e) and motoneurons (b, d, f) at 4 weeks after VRA injury. Significantly more ChAT-immunolabeled motoneurons co-localized with activated caspase-3 (large arrows) than PPNs (p<0.05). Small arrows indicate no co-localization. Scale bar = 30 µm for a, c, e; 20 µm for b, d, f.