A Conditioning Lesion Provides Selective Protection in a Rat Model of Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is neurodegenerative disease characterized by muscle weakness and atrophy due to progressive motoneuron loss. The death of motoneuron is preceded by the failure of neuromuscular junctions (NMJs) and axonal retraction. Thus, to develop an effective ALS therapy you must simultaneously preserve motoneuron somas, motor axons and NMJs. A conditioning lesion has the potential to accomplish this since it has been shown to enhance neuronal survival and recovery from trauma in a variety of contexts. rats that received a conditioning lesion was delayed and less severe. These improvements in motor function corresponded to greater motoneuron survival, reduced motor axonopathy, and enhanced NMJ maintenance at disease end-stage. Furthermore, the increased NMJ maintenance was selective for muscle compartments innervated by the most resilient (slow) motoneuron subtypes, but was absent in muscle compartments innervated by the most vulnerable (fast fatigable) motoneuron subtypes.These findings support the development of strategies aimed at mimicking the conditioning lesion effect to treat ALS as well as underlined the importance of considering the heterogeneity of motoneuron sub-types when evaluating prospective ALS therapeutics

Conditioning lesion protects motor neurons at end-stage.

<p>(A–C) Representative examples of Nissl stained ventral horns from the L4–6 spinal cord of 10 wk un-operated, Crush, and Sham. (D) The mean (± SE) density of motor neurons per section compared between 10 wk, Crush, Sham and the contralateral side of Crush (Contra). (E) The mean (± SE) area of motor neuron somas shown for each group. (F–I) Histograms show the distribution of motor neuron areas for each group. Scale bar represents 250 µm. #, <i>P</i><0.01; *, <i>P</i><0.05.</p

Conditioning lesion reduces the decline of motor function.

<p>(A) The mean (± SE) hindlimb grip strength for Crush (grey circles) and Sham (black circles). (B) The mean (± SE) BBB locomotor score relative for Crush and Sham. (C) The mean (± SE) ALS motor score for Crush and Sham. (D) The mean (± SE) body weight for Crush and Sham. The number of animal assessed in each group over time is indicated at the bottom of graph D. #, <i>P</i><0.01; *, <i>P</i><0.05.</p

Conditioning lesion preserves ventral root axons at end-stage.

<p>(A–C) Photomicrographs of L4 VRs stained with toluidine blue and taken at either 20 or 100X. (D) The mean (± SE) number of large (black bars; >8 µm) and small (white bars; ≤8 µm) myelinated axons. Scale bar represents 150 µm (20X) or 25 µm (100X). #, <i>P</i><0.01; *, <i>P</i><0.05.</p

Conditioning lesion selectively preserves NMJs at end-stage.

<p>(A–B) Motor endplates were stained with α-bungarotoxin (red); axons were stained with antibodies for synaptophysin and class III β-tubulin (green). (C) A diagram depicting MG muscle compartments containing mixed (fast & slow) or only fast muscle fibers. (D–E) The mean (±SE) percentage of innervated NMJs was quantified for the mixed and fast muscle compartments of the MG muscle from 10 wk, Crush, and Sham. Scale bar represents 50 µm (A, B) or 1 mm (C). #, <i>P</i><0.01; *, <i>P</i><0.05.</p