A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction

K+ channels containing Kv1.1 α subunits, which become prevalent at internodes in demyelinated axons, may underlie their dysfunctional conduction akin to muscle weakness in multiple sclerosis. Small inhibitors were sought with selectivity for the culpable hyper-polarizing K+ currents. Modeling of interactions with the extracellular pore in a Kv1.1-deduced structure identified diaryldi(2-pyrrolyl)methane as a suitable scaffold with optimized alkyl ammonium side chains. The resultant synthesized candidate [2,2′-((5,5′(di-p-topyldiaryldi(2-pyrrolyl)methane)bis(2,2′carbonyl)bis(azanediyl)) diethaneamine·2HCl] (8) selectively blocked Kv1.1 channels (IC50 ≈ 15 μM) recombinantly expressed in mammalian cells, induced a positive shift in the voltage dependency of K+ current activation, and slowed its kinetics. It preferentially inhibited channels containing two or more Kv1.1 subunits regardless of their positioning in concatenated tetramers. In slices of corpus callosum from mice subjected to a demyelination protocol, this novel inhibitor improved neuronal conduction, highlighting its potential for alleviating symptoms in multiple sclerosis

Anodal tDCS does not enhance the learning of the sequential finger-tapping task by motor imagery practice in healthy older adults

International audienceBackground Motor imagery practice (MIP) and anodal transcranial direct current stimulation (a-tDCS) are innovative methods with independent positive influence on motor sequence learning (MSL) in older adults. Objective The present study investigated the effect of MIP combined with a-tDCS over the primary motor cortex (M1) on the learning of a finger tapping sequence of the non-dominant hand in healthy older adults. Methods Thirty participants participated in this double-blind sham-controlled study. They performed three MIP sessions, one session per day over three consecutive days and a retention test 1 week after the last training session. During training / MIP, participants had to mentally rehearse an 8-element finger tapping sequence with their left hand, concomitantly to either real ( a-tDCS group) or sham stimulation ( sham-tDCS group). Before and after MIP, as well as during the retention test, participants had to physically perform the same sequence as fast and accurately as possible. Results Our main results showed that both groups (i) improved their performance during the first two training sessions, reflecting acquisition/on-line performance gains, (ii) stabilized their performance from one training day to another, reflecting off-line consolidation; as well as after 7 days without practice, reflecting retention, (iii) for all stages of MSL, there was no significant difference between the sham-tDCS and a-tDCS groups. Conclusion This study highlights the usefulness of MIP in motor sequence learning for older adults. However, 1.5 mA a-tDCS did not enhance the beneficial effects of MIP, which adds to the inconsistency of results found in tDCS studies. Future work is needed to further explore the best conditions of use of tDCS to improve motor sequence learning with MIP

Data_Sheet_1_Anodal tDCS does not enhance the learning of the sequential finger-tapping task by motor imagery practice in healthy older adults.docx

BackgroundMotor imagery practice (MIP) and anodal transcranial direct current stimulation (a-tDCS) are innovative methods with independent positive influence on motor sequence learning (MSL) in older adults.ObjectiveThe present study investigated the effect of MIP combined with a-tDCS over the primary motor cortex (M1) on the learning of a finger tapping sequence of the non-dominant hand in healthy older adults.MethodsThirty participants participated in this double-blind sham-controlled study. They performed three MIP sessions, one session per day over three consecutive days and a retention test 1 week after the last training session. During training / MIP, participants had to mentally rehearse an 8-element finger tapping sequence with their left hand, concomitantly to either real (a-tDCS group) or sham stimulation (sham-tDCS group). Before and after MIP, as well as during the retention test, participants had to physically perform the same sequence as fast and accurately as possible.ResultsOur main results showed that both groups (i) improved their performance during the first two training sessions, reflecting acquisition/on-line performance gains, (ii) stabilized their performance from one training day to another, reflecting off-line consolidation; as well as after 7 days without practice, reflecting retention, (iii) for all stages of MSL, there was no significant difference between the sham-tDCS and a-tDCS groups.ConclusionThis study highlights the usefulness of MIP in motor sequence learning for older adults. However, 1.5 mA a-tDCS did not enhance the beneficial effects of MIP, which adds to the inconsistency of results found in tDCS studies. Future work is needed to further explore the best conditions of use of tDCS to improve motor sequence learning with MIP.</p

A Rational Design of a Selective Inhibitor for Kv1.1 Channels Prevalent in Demyelinated Nerves That Improves Their Impaired Axonal Conduction

K⁺ channels containing Kv1.1 α subunits, which become prevalent at internodes in demyelinated axons, may underlie their dysfunctional conduction akin to muscle weakness in multiple sclerosis. Small inhibitors were sought with selectivity for the culpable hyper-polarizing K⁺ currents. Modeling of interactions with the extracellular pore in a Kv1.1-deduced structure identified diaryldi­(2-pyrrolyl)­methane as a suitable scaffold with optimized alkyl ammonium side chains. The resultant synthesized candidate [2,2′-((5,5′(di-<i>p</i>-topyldiaryldi­(2-pyrrolyl)­methane)­bis­(2,2′carbonyl)­bis­(azanediyl)) diethaneamine·2HCl] (<b>8</b>) selectively blocked Kv1.1 channels (IC₅₀ ≈ 15 μM) recombinantly expressed in mammalian cells, induced a positive shift in the voltage dependency of K⁺ current activation, and slowed its kinetics. It preferentially inhibited channels containing two or more Kv1.1 subunits regardless of their positioning in concatenated tetramers. In slices of corpus callosum from mice subjected to a demyelination protocol, this novel inhibitor improved neuronal conduction, highlighting its potential for alleviating symptoms in multiple sclerosis