Role of the NMDA-receptor in Prepulse Inhibition in the Rat

Kynurenic acid (KYNA) is an endogenous metabolite of tryptophan. Studies have revealed increased brain KYNA levels in patients with schizophrenia. Prepulse inhibition (PPI) is a behavioral model for sensorimotor gating and found to be reduced in schizophrenia. Previous studies have shown that pharmacologically elevated brain KYNA levels disrupt PPI in the rat. The aim of the present study was to investigate the receptor(s) involved in this effect. Rats were treated with different drugs selectively blocking each of the sites that KYNA antagonizes, namely the glutamate recognition site of the N-methyl-D-aspartate receptor (NMDAR), the α7* nicotinic acetylcholine receptor (α7nAChR) and the glycine site of the NMDAR. Kynurenine (200 mg/kg) was given to replicate the effects of increased levels of KYNA on PPI. In order to block the glutamate recognition site of the NMDAR, CGS 19755 (10 mg/kg) or SDZ 220–581 (2.5 mg/kg) were administered and to antagonize the α7nAChR methyllycaconitine (MLA; 6 mg/kg) was given. L-701,324 (1 and 4 mg/kg) or 4-Chloro-kynurenine (4-Cl-KYN; 25, 50 and 100 mg/kg), a drug in situ converted to 7-Chloro-kynurenic acid, were used to block the glycine-site of the NMDAR. Administration of SDZ 220-581 or CGS 19755 was associated with a robust reduction in PPI, whereas L-701,324, 4-Cl-KYN or MLA failed to alter PPI. Kynurenine increased brain KYNA levels 5-fold and tended to decrease PPI. The present study suggests that neither antagonism of the glycine-site of the NMDA receptor nor antagonism of the α7nAChR disrupts PPI, rather with regard to the effects of KYNA, blockade of the glutamate recognition-site is necessary to reduce PPI.

Failure of the competitive N-methyl-d-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two Phase III clinical trials

Object. Excessive activity of excitatory amino acids released after head trauma has been demonstrated to contribute to progressive injury in animal models and human studies. Several pharmacological agents that act as antagonists to the glutamate receptor have shown promise in limiting this progression. The efficacy of the N-methyl-d-aspartate receptor antagonist Selfotel (CGS 19755) was evaluated in two parallel studies of severely head injured patients, defined as patients with postresuscitation Glasgow Coma Scale scores of 4 to 8.Methods. A total of 693 patients were prospectively enrolled in two multicenter double-blind studies. Comparison between the treatment groups showed no significant difference with regard to demographic data, previous incidence of hypotension, and severity of injury. As the study progressed, the Safety and Monitoring Committee became concerned about possible increased deaths and serious brain-related adverse events in the treatment arm of the two head injury trials, as well as deaths in the two stroke trials being monitored concurrently. The Selfotel trials were stopped prematurely because of this concern and because an interim efficacy analysis indicated that the likelihood of demonstrating success with the agent if the studies had been completed was almost nil.Conclusions. Subsequently, more complete data analysis revealed no statistically significant difference in mortality rates in all cases between the two treatment groups in the head injury trials. In this report the authors examine the studies in detail and discuss the potential application of the data to future trial designs.

Lack of Neuronal Vacuolation and Necrosis in Monkeys Treated with Selfotel (CGS 19755), A Competitive N-methyl-D-aspartate Receptor Antagonist

Several N-methyl-D-aspartate (N M D A) receptor antagonists are being developed to reduce overstimulation of N M D A receptors by excessive glutamate, released as a consequence of acute cerebral hypoxial ischemia after stroke or head trauma. N M D A receptor antagonists, including Selfotel (C G S 19755), have been demonstrated to cause neuronal vacuolation and neuronal necrosis in the retrosplenial and / or posterior cingulate cerebral cortices of rats; however, little in formation is available on their effects on the cerebral cortices of primates. Cynomolgus monkeys were treated with single parenteral doses of N M D A antagonists (Selfotel or M K-801). Monkeys were administered intravenous doses of Selfotel at 2 or 20 mg/kg and were necropsied 4, 24, or 72 h postdose. Additional monkeys, administered M K-801 subcutaneously at 0.25 mg/kg, were necropsied 4 or 72 h postdose. Overt, centrally mediated clinical signs occurred in both Selfote l- and M K-801–treated monkeys (e.g., at axia, hypoactivity, salivation, convulsions, disorientation, dyspnea, apnea, recumbency, and cyanosis). Brains were perfusion-fixed in situ with 1% paraformaldehyde and 1.5% glutaraldehyde in pyrophosphate buffer. Brain sections from the animals necropsied 4 and 24 h postdose we reembedded in plastics (Durcupan) and paraffin, cut at 1 or 2 μm thickness, and stained with Richardson's stain. Brains from the animals necropsie d 72 h postdose were embedded in paraffin, cut at 4 μm, and stained with hematoxylin and eosin. Microscopic examination of posterior cingulate and/or retrosplenial cerebral cortices from monkey streated with Selfotel or M K-801 did not reveal any neuronal vacuolation or necrosis.