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Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron (Mn) disease without effective cure currently available. Death of MNs in ALS is preceded by failure of neuromuscular junctions and axonal retraction. Neuregulin 1 (NRG1) is a neurotrophic factor highly expressed in MNs and neuromuscular junctions that support axonal and neuromuscular development and maintenance. NRG1 and its ErbB receptors are involved in ALS. Reduced NRG1 expression has been found in ALS patients and in the ALS SOD1(G93A) mouse model; however, the expression of the isoforms of NRG1 and its receptors is still controversial. Due to the reduced levels of NRG1 type III (NRG1-III) in the spinal cord of ALS patients, we used gene therapy based on intrathecal administration of adeno-associated virus to overexpress NRG1-III in SOD1(G93A) mice. The mice were evaluated from 9 to 16 weeks of age by electrophysiology and rotarod tests. At 16 weeks, samples were harvested for histological and molecular analyses. Our results indicate that overexpression of NRG1-III is able to preserve neuromuscular function of the hindlimbs, improve locomotor performance, increase the number of surviving MNs, and reduce glial reactivity in the treated female SOD1(G93A) mice. Furthermore, the NRG1-III/ErbB4 axis appears to regulate MN excitability by modulating the chloride transporter KCC2 and reduces the expression of the MN vulnerability marker MMP-9. However, NRG1-III did not have a significant effect on male mice, indicating relevant sex differences. These findings indicate that increasing NRG1-III at the spinal cord is a promising approach for promoting MN protection and functional improvement in ALS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00811-7) contains supplementary material, which is available to authorized users.

Minocycline has been reported to be both beneficial and detrimental for nerve regeneration after peripheral nerve injury. By reducing the inflammatory response, minocycline administration reduces pain and has neuroprotective effects, but it also inhibits Wallerian degeneration in the distal stump, and reduces microglia and macrophages activity on motor and sensory neurons, which could reduce their intrinsic regenerative capacity. The aim of this study was to determine if the administration of minocycline after nerve injury inhibits the regenerative capacity of motoneurons and sensory neurons after a conditioning lesion. We used two groups of mice: a control group and a group treated with minocycline (30 mg kg-1 ip twice daily). We labeled motor and sensory neurons that had regenerated to a distance of 3 mm in a predegenerated graft, after a conditioning lesion. Our results indicate that minocycline administration is not detrimental for nerve regeneration. Indeed, it even promoted a slight, no significant increase 7 days after the nerve graft. These results indicate that minocycline, given at a dose able to reduce pain after peripheral nerve injury, does not interfere with the intrinsic growth capacity of injured peripheral neurons. Anat Rec, 301:1638-1645, 2018. © 2018 Wiley Periodicals, Inc.

Minocycline has been reported to be both beneficial and detrimental for nerve regeneration after peripheral nerve injury. By reducing the inflammatory response, minocycline administration reduces pain and has neuroprotective effects, but it also inhibits Wallerian degeneration in the distal stump, and reduces microglia and macrophages activity on motor and sensory neurons, which could reduce their intrinsic regenerative capacity. The aim of this study was to determine if the administration of minocycline after nerve injury inhibits the regenerative capacity of motoneurons and sensory neurons after a conditioning lesion. We used two groups of mice: a control group and a group treated with minocycline (30 mg kg