Neuroprotective effects of melanocortins in CNS injury.

New compounds having affinity to various melanocortin receptors have recently been identified as possible neuroprotective agents. This review is focused on the role of neuroprotective effects of melanocortins in CNS injury and repair mechanisms. Using selective non-peptidic compounds with varying affinity to melanocortin receptors, our laboratory has shown their anti-edematous effects in the spinal cord injury. This effect of the compounds is related with their ability to attenuate blood-spinal cord barrier permeability. The functional significance and possible therapeutic strategies of these compounds in CNS injury are discussed.

Neuroprotective effects of melanocortins in experimental spinal cord injury. An experimental study in the rat using topical application of compounds with varying affinity to melanocortin receptors.

The possibility that local administration of low molecular weight non-peptide compounds with varying affinities at melanocortin receptors in the spinal cord will influence pathophysiological outcome of spinal cord injury (SCI) was examined in a rat model. Five new Melacure compounds ME10092, ME10354, ME10393, ME10431 and ME10501 were used in this investigation. Each compound was dissolved in saline and tested at 3 different doses, i.e. 1 microg, 5 microg and 10 microg total dose in 10 microl applied topically 5 min after SCI. The animals were allowed to survive 5 h and trauma induced edema formation, breakdown of the blood-spinal cord barrier (BSCB) and cell injuries were examined and compared with untreated injured rats. A focal SCI inflicted by an incision into the right dorsal horn of the T10-11 segments resulted in marked edema formation, breakdown of the BSCB to Evans blue albumin and caused profound nerve cell injury in the T9 and the T12 segments. Topical application of ME10501 (a compound with high affinity at melanocortin, MC-4 receptors) in high doses (10 microg) resulted in most marked neuroprotection in the perifocal spinal cord (T9 and T12) segments. On the other hand, only a mild or no effect on spinal cord pathology was observed in the traumatized animals that received ME10092, ME10354, ME10393 and ME10431 at 3 different doses. These observations suggest that non-peptide compounds with varying affinity to melanocortin receptors are able to influence the pathophysiology of SCI. Furthermore, compounds acting at melanocortin, MCR4 receptors are capable to induce neuroprotection in spinal cord following trauma.

Low molecular weight compounds with affinity to melanocortin receptors exert neuroprotection in spinal cord injury--an experimental study in the rat.

The possibility that five new low molecular weight compounds with varying affinity and selectivity to the melanocortin receptors will exert neuroprotective effects in the spinal cord injury (SCI) induced edema formation and cell damage was examined in a rat model. A focal trauma of the rat spinal cord made by an incision into the right dorsal horn (T10-11) resulted in profound edema formation, leakage of Evans blue albumin and cell injury of the T9 segment at 5 h. Topical application of the Melacure compound ME10501 in high doses (10 microg in 10 microl) given 5 min after SCI resulted in most significant neuroprotection of the T9 segment of the cord compared to other compounds. Thus, marked reduction in water content, leakage of Evans blue albumin, and cell injury were observed in ME10501 treated traumatised rats. These observations suggest that the non-peptide compound ME10501 with affinity to the melanocortin receptor MC4 is capable to induce neuroprotection in the spinal cord following trauma not reported earlier.

Activation of the GABA(B) receptor inhibits transient lower esophageal sphincter relaxations in dogs.

BACKGROUND & AIMS: Transient lower esophageal sphincter relaxation (TLESR) appears to be the most frequent motor event responsible for gastroesophageal reflux. Because TLESRs are considered to be triggered by activation of gastric mechanoreceptors, and because the gamma-aminobutyric acid type B (GABA(B))-receptor agonist baclofen is known to inhibit transmitter release from mechanosensitive afferents, the effects of baclofen on TLESRs in the dog were assessed. METHODS: A total of 183 recordings of the pharyngeal, esophageal, lower esophageal sphincter, and gastric pressures as well as measurement of esophageal pH were performed in 15 awake dogs. Racemic baclofen, its enantiomers, and the GABA(B)-receptor antagonist CGP36742 were administered before stimulation of TLESRs by a liquid meal and air insufflation. The pharmacodynamics of baclofen were compared with its pharmacokinetics. RESULTS: Baclofen dose-dependently inhibited TLESRs, with a 50% effective dose (ED(50)) of 1.0 micromol/kg after intravenous administration. The maximal inhibition amounted to approximately 80%. Intragastric baclofen was almost equally effective (ED(50), 1.8 micromol/kg), compatible with the complete oral availability of the drug (100%). The inhibitory effect of baclofen resided in the pharmacologically active R enantiomer, and CGP36742 reduced some of the effects of baclofen. CONCLUSIONS: Baclofen is a potent and efficacious inhibitor of TLESRs and reflux in the dog. Activation of the GABA(B) receptor may be a new approach to the treatment of reflux disease.

Sensitive method for the determination of baclofen in plasma by means of solid-phase extraction and liquid chromatography-tandem mass spectrometry.

A simple and sensitive method for the determination of baclofen in plasma is described. Baclofen and the internal standard, KM 08205, were isolated from plasma by solid-phase extraction using C18 material. After separation by reversed-phase liquid chromatography, the analytes were detected with tandem mass spectrometry. The extraction procedure was optimised regarding the solid-phase extraction material, the pH in the conditioning solution and the washing volume. The method was proven to be selective and sensitive with an absolute recovery of about 95%, a relative standard deviation below 5% and a limit of quantification of 10 nmol/1.