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Epilepsy is a neurological disorder characterized by recurrent seizures, which result from excessive, synchronous discharges of neurons in different brain areas. In about 30% of cases, epileptic discharges, which vary in their etiology and symptomatology, are difficult to treat with conventional drugs. Ferroptosis is a newly defined iron-dependent programmed cell death, characterized by excessive accumulation of lipid peroxides and reactive oxygen species. Evidence has been provided that ferroptosis is involved in epilepsy, and in particular in those forms resistant to drugs. Here, whole cell patch clamp recordings, in current and voltage clamp configurations, were performed from layer IV principal neurons in cortical slices obtained from adult mouse brain. Application of the ferroptosis inducer RAS-selective lethal 3 (RSL3) induced interictal epileptiform discharges which started at RSL3 concentrations of 2 mM and reached a plateau at 10 mM. This effect was not due to changes in active or passive membrane properties of the cells, but relied on alterations in synaptic transmission. In particular, interictal discharges were dependent on the excessive excitatory drive to layer IV principal cells, as suggested by the increase in frequency and amplitude of spontaneously occurring excitatory glutamatergic currents, possibly dependent on the reduction of inhibitory GABAergic ones. This led to an excitatory/inhibitory unbalance in cortical circuits. Interictal bursts could be prevented or reduced in frequency by the lipophilic antioxidant Vitamin E (30 mM). This study allows identifying new targets of ferroptosis-mediated epileptic discharges opening new avenues for the treatment of drug-resistant forms of epilepsy. [ABSTRACT FROM AUTHOR]

Muscle paralysis after spinal cord injury is partly caused by a loss of brainstem-derived serotonin (5-HT), which normally maintains motoneuron excitability by regulating crucial persistent calcium currents. Here we examine how over time motoneurons compensate for lost 5-HT to regain excitability. We find that, months after a spinal transection in rats, changes in posttranscriptional editing of [5-HT.sub.2C] receptor mRNA lead to increased expression of [5- HT.sub.2C] receptor isoforms that are spontaneously active (constitutively active) without 5-HT. Such constitutive receptor activity restores large persistent calcium currents in motoneurons in the absence of 5-HT. We show that this helps motoneurons recover their ability to produce sustained muscle contractions and ultimately enables recovery of motor functions such as locomotion. However, without regulation from the brain, these sustained contractions can also cause debilitating muscle spasms. Accordingly, blocking constitutively active [5-HT.sub.2C] receptors with SB206553 or cyproheptadine, in both rats and humans, largely eliminates these calcium currents and muscle spasms, providing a new rationale for antispastic drug therapy., Severe spinal cord injury (SCI) causes an immediate paralysis of muscles innervated by motoneurons directly caudal to the injury site. This results not only from a loss of supraspinal tracts [...]

Background: Preclinical studies underlined the relevance of Nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor pathway in the pathogenesis of Parkinson's disease (PD).Objective: The objective of this study was to explore Nrf2 pathway in vivo in PD, looking for novel disease biomarkers and therapeutic targets.Methods: The levels of Nrf2, the downstream effectors (NAD(P)H dehydrogenase [quinone] 1 (Nqo1) enzyme, glutathione metabolism enzymes Glutamate-cysteine ligase (GCL) and Glutathione Reductase (GR)), the upstream activators (redox state and mitochondrial dysfunction), and α-synuclein oligomers were assessed in the blood leukocytes of PD patients comparatively to controls. Biochemical data were correlated to clinical parameters.Results: In PD, Nrf2 was highly transcribed and expressed as well as its target effectors. The mitochondrial complex I activity was reduced and the oxidized form of glutathione prevailed, disclosing the presence of pathway's activators. Also, α-synuclein oligomers levels were increased. Nrf2 transcript and oligomers levels correlated with PD duration.Conclusions: Blood leukocytes mirror pathogenic mechanisms of PD, showing the systemic activation of the Nrf2 pathway and its link with synucleinopathy and clinical events. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Paired corticospinal-motoneuronal stimulation increases maximal voluntary activation of human adductor pollicis. J Neurophysiol 119: 369-376, 2018. First published October 18, 2017; doi:10.1152/jn.00919.2016.--Paired corticospinal-motoneuronal stimulation (PCMS), which delivers repeated pairs of transcranial magnetic stimuli (TMS) and maximal motor nerve stimuli, can alter corticospinal transmission to lowthreshold motoneurons in the human spinal cord. To determine whether similar changes occur for high-threshold motoneurons, we tested whether maximal voluntary activation and force can be affected by PCMS in healthy individuals. On 2 separate days, healthy participants (n - 14) performed brief thumb adduction maximal voluntary contractions (MVCs) before and after a control protocol (TMS only) or PCMS designed to facilitate corticospinal transmission to adductor pollicis. Peripheral nerve stimulation alone was not performed. During each MVC, a superimposed twitch was elicited by a supramaximal stimulus delivered to the ulnar nerve. With muscles relaxed following the maximal contraction, a similar stimulus elicited a resting twitch. Voluntary activation was calculated as (1 ± superimposed twitch/resting twitch) x 100%. Although voluntary activation decreased over time in both conditions, the decrease was less after PCMS (-0.4 ± 4.1%) than after the control protocol (-4.9 ± 4.9%; P = 0.007). This was supported by a greater increase in electromyographic response after PCMS than control (7 ± 13% vs. -3 ± 10%; P = 0.043). However, maximal force was not affected. The findings indicate a modest effect of PCMS on maximal neural drive to adductor pollicis, suggesting that PCMS can affect corticospinal transmission to high-threshold motoneurons. NEW & NOTEWORTHY Paired corticospinal-motoneuronal stimulation (PCMS) induces changes in the human spinal cord. To date, the reported effects of PCMS have been limited to low-threshold motoneurons and low-force tasks in healthy and spinal cord injured individuals. For the first time, we show that these plastic changes are not limited to lower threshold motoneurons, but occur across the entire motoneuron pool as demonstrated by the increases in voluntary activation and muscle activity during maximal voluntary contractions of adductor pollicis. [ABSTRACT FROM AUTHOR]

Key points In the adult turtle spinal cord, action potential generation in motoneurones is inhibited by spillover of serotonin to extrasynaptic serotonin 1A (5-HT1A) receptors at the axon initial segment. We explored whether ingestion of the 5-HT1A receptor partial agonist, buspirone, decreases motoneurone excitability in humans., Following ingestion of buspirone, two tests of motoneurone excitability showed decreases. F-wave areas and persistence in an intrinsic muscle of the hand were reduced, as was the area of cervicomedullary motor evoked potentials in biceps brachii., Our findings suggest that activation of 5-HT1A receptors depresses human motoneurone excitability. Such a depression could contribute to decreased motoneurone output during fatiguing exercise if there is high serotonergic drive to the motoneurones., Abstract Intense serotonergic drive in the turtle spinal cord results in serotonin spillover to the axon initial segment of the motoneurones where it activates serotonin 1A (5-HT1A) receptors and inhibits generation of action potentials. We examined whether activation of 5-HT1A receptors decreases motoneurone excitability in humans by determining the effects of a 5-HT1A receptor partial agonist, buspirone, on F waves and cervicomedullary motor evoked potentials (CMEPs). In a placebo-controlled double-blind study, 10 participants were tested on two occasions where either placebo or 20 mg of buspirone was administered orally. The ulnar nerve was stimulated supramaximally to evoke F waves in abductor digiti minimi (ADM). CMEPs and the maximal M wave were elicited in biceps brachii by cervicomedullary stimulation and brachial plexus stimulation, respectively. Following buspirone intake, F-wave area and persistence, as well as CMEP area, were significantly decreased. The mean post-pill difference in normalized F-wave areas and persistence between buspirone and placebo days was -27% (-42, -12; 95% confidence interval) and -9% (-16, -2), respectively. The mean post-pill difference in normalized CMEP area between buspirone and placebo days showed greater variation and was -31% (-60, -2). In conclusion, buspirone reduces motoneurone excitability in humans probably via activation of 5-HT1A receptors at the axon initial segment. This has implications for motor output during high drive to the motoneurones when serotonin may spill over to these inhibitory receptors and consequently inhibit motoneurone output. Such a mechanism could potentially contribute to fatigue with exercise. [ABSTRACT FROM AUTHOR]