Neuroinflammation is a major hallmark of amyotrophic lateral sclerosis (ALS), which is currently untreatable. Several anti-inflammatory compounds have been evaluated in patients and in animal models of ALS, but have been proven disappointing in part because effective targets have not yet been identified. Cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), as a foldase is beneficial intracellularly, but extracellularly has detrimental functions. We found that extracellular PPIA is a mediator of neuroinflammation in ALS. It is a major inducer of matrix metalloproteinase 9 and is selectively toxic for motor neurons. High levels of PPIA were found in the CSF of SOD1 G93A mice and rats and sporadic ALS patients, suggesting that our findings may be relevant for familial and sporadic cases. A specific inhibitor of extracellular PPIA, MM218, given at symptom onset, rescued motor neurons and extended survival in the SOD1 G93A mouse model of familial ALS by 11 d. The treatment resulted in the polarization of glia toward a prohealing phenotype associated with reduced NF-B activation, proinflammatory markers, endoplasmic reticulum stress, and insoluble phosphorylated TDP-43. Our results indicates that extracellular PPIA is a promising druggable target for ALS and support further studies to develop a therapy to arrest or slow the progression of the disease in patients.

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We performed transcranial magnetic stimulation of the motor cortex in 22 left-handed and 25 right-handed subjects during active contraction of a small hand muscle. Motor evoked potentials had the same latency, amplitude and threshold on both sides of the body, whilst the silent period duration was shorter in the dominant hand. Silent periods elicited by nerve and brainstem stimulation were the same in both hands. Since the latter part of the cortical silent period is due mainly to withdrawal of corticospinal input to spinal motoneurones, we speculate that the results are compatible with the suggestion that tonic contractions of the non-dominant hand are associated with a greater involvement of the corticospinal tract than those of the dominant hand. It also seems likely that there is an asymmetry in the excitability of cortical inhibitory mechanisms with those responsible for the cortical silent period being less excitable in the dominant motor cortex.

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Motor potentials of the bulbocavernosus muscle were recorded in 17 healthy subjects after transcranial and lumbar magnetic stimulation. The latencies (SD) were respectively: (1-8) and 5 9 (04) ms. The central conduction time was 17-0 (2 5) ms. The bulbocavernosus reflex presented an onset at 34-5 (3 3) ms and a negative peak at 43-1 (3 9) ms. The cortical pudendal evoked potential was W shaped: the first peak had a latency of 35 4 (2 8) ms. The concurrent recording of motor potentials, bulbocavernosus reflex, pudendal evoked potentials gives a measure of peripheral and central, afferent and efferent neurological pathways related to pudendal nerve function.