Ion Channel Modulation as the Basis for Neuroprotective Action of MS‐153

Abstract

MS-153, (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline, is a new neuroprotective drug. Recent data in the literature suggest that it inhibits glutamate accumulation occurring during ischemia and the translocation of protein kinase C gamma (PKC gamma). The present study was undertaken to prove the hypothesis that MS-153 blocks neuroreceptors and ion channels involved in glutamate accumulation. Neurons isolated from rat dorsal root ganglia and frontal cortex were used for recording channel currents by the whole-cell patch clamp technique. The effects of bath-applied MS-153 were examined on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels and high voltage-gated calcium channels of dorsal root ganglion neurons, and channels activated by glutamate, N-methyl-D-aspartate (NMDA), kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxarole propionic acid (AMPA), gamma-aminobutyric acid (GABA) and acetylcholine (ACh) in cortical neurons. MS-153 at a concentration of 300 microM had no effect on either tetrodotoxin-sensitive or tetrodotoxin-resistant sodium channels. High voltage-gated calcium channels were either suppressed or not affected by 1-300 microM MS-153. The variable blocking effect of MS-153 was due to the variable activity of intracellular components in individual neurons, especially that of PKC, whose translocation is known to be inhibited by MS-153. When 100 nM phorbol 12-myristate-13-acetate (PMA) was applied to neurons, MS-153 suppressed the calcium channel current more frequently. Calphostin C (0.5 microM), a specific PKC inhibitor, applied intracellularly via recording patch pipette, completely abolished MS-153 suppression of the calcium channel current. Currents induced by glutamate, NMDA, kainate, AMPA, GABA or ACh were not affected by MS-153 at 300 microM. It was concluded that MS-153 inhibited high voltage-gated calcium channels through interactions with PKC, thereby preventing massive release of glutamate from nerve terminals in ischemic conditions.

Neuroprotective Effects of the Glutamate Transporter Activator (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following Traumatic Brain Injury in the Adult Rat

“…MS-153 can block voltage-gated calcium channels through a mechanism that is protein kinase C (PKC)-dependent 46 ; MS-153 inhibits the translocation and activation of PKC-c that leads to the suppression of the calcium channel current. 45 Calcium channel blockers such as emopamil 79 and nimodipine 80 have been shown to be neuroprotective in TBI.…”

“…Further, the decrease in calpain-mediated spectrin proteolysis would suggest that the effects of MS-153 are mediated via a reduction of calcium influx into injured cells. 46 Several classes of compounds including NMDA receptor antagonists 81 and compounds that target calcium influx, 79,82 have been shown to ameliorate cellular damage and neurologic deficits, as well as cognitive decline and motor impairments caused by TBI. In models of brain injury, glutamate receptor antagonists, such as kynurenate, 83 NBQX, and CGS 19755, 84 have been reported to partially ameliorate cytoskeletal injury with preserved immuno-labeling of MAP-2 and to reduce the accumulation of calpain-cleaved spectrin byproducts.…”

“…In addition to reducing elevated brain glutamate levels induced by middle cerebral artery occlusion, 45 MS-153 can inhibit voltage-gated calcium channels and prevent ischemia-induced release of glutamate from nerve terminals. 46 MS-153 has been shown to affect other conditions that are believed to involve excessive glutamate signaling, such as the inhibition of morphine tolerance and dependence, 47 the attenuation of behavioral sensitization development to phencyclidine, 48,49 an anxiolytic effect in fear conditioning, 50 and attenuation of the conditioned rewarding effects of morphine, methamphetamine, and cocaine. 51 MS-153 was recently suggested to have potential as a therapeutic drug for the treatment of alcohol dependence.…”

A Simple, Efficient, and Highly Enantioselective Synthesis of MS‐153 Employing a Chiral Silane Lewis Acid‐Promoted Acylhydrazone‐Enol Ether [3+2] Cycloaddition

“…[6] Although the exact mechanism(s) by which MS-153 exerts its neuroprotective effects is-A C H T U N G T R E N N U N G (are) not entirely understood, it has been suggested that it inhibits high voltage-gated calcium channels, thereby inhibiting release of glutamate from nerve terminals in ischemic conditions. [6] Due to this intriguing activity we decided to undertake an investigation geared towards an efficient asymmetric synthesis of MS-153.…”

“…[6] Although the exact mechanism(s) by which MS-153 exerts its neuroprotective effects is-A C H T U N G T R E N N U N G (are) not entirely understood, it has been suggested that it inhibits high voltage-gated calcium channels, thereby inhibiting release of glutamate from nerve terminals in ischemic conditions. [6] Due to this intriguing activity we decided to undertake an investigation geared towards an efficient asymmetric synthesis of MS-153. Due to its relatively simple structure we set at the outset several boundary conditions for the synthesis including only a very small number of operationally trivial, inexpensive, and environmentally benign steps that all proceed with excellent efficiency and, where relevant, near-perfect enantioselectivity.…”