ACEA 1021: flip or flop?

Inasmuch as glutamate is the main excitatory neurotransmitter in the central nervous system, strategies aimed at counteracting glutamate excitotoxicity, which is at least partially involved in many acute neurologic, chronic neurodegenerative and psychiatric diseases, are challenging. Blockade of the NMDA receptor was identified as one way of achieving selective antagonism and overcoming glutamate neurotoxicity, yet not without liabilities. Glycine site antagonism of the NMDA receptor in 1987 offered a significant advance in blocking this receptor because such drugs were shown to lack most of the side effects, such as memory impairment, ataxia, lack of motor coordination and psychotomimetic effects, which accompanied competitive and non-competitive NMDA receptor antagonists. To date, much has been done to improve the structure-activity relationship (SAR) of compounds resulting in the synthesis of ACEA 1021. It is unclear, however, whether further chemical substitutions will lead to an improved compound. Many studies have been performed with ACEA 1021 and although there are much in vitro and in vivo data to support its neuroprotective effects and improved safety profile, there is very little published information regarding its clinical pharmacology. In order to properly evaluate the true potential for ACEA 1021 in acute and chronic CNS disorders additional longer term safety and efficacy data in humans are needed.

In vivo neuroprotective effects of ACEA 1021 confirmed by magnetic resonance imaging in ischemic stroke.

The neuroprotective activity of ACEA 1021 (5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione; licostinel), a selective antagonist at the strychnine-insensitive glycine site associated with the NMDA receptor complex, has been investigated in various models of focal cerebral ischemia. In isoflurane-anaesthesised Wistar rats with permanent ipsilateral carotid artery ligation and transient middle cerebral artery occlusion (duration of occlusion, 2 h) followed by reperfusion (24 h), intravenous administration of ACEA 1021 (bolus: 10 mg/kg, 15 min after the onset of middle cerebral artery occlusion; infusion: 7 mg/kg/h for 6 h beginning 30 min after occlusion of the artery) produced a 32% reduction in infarct volume. Similarly, in Sprague-Dawley rats with transient middle cerebral artery occlusion (2 h) followed by 24 h of reperfusion, identical treatment with ACEA 1021 decreased infarct size by 39%. Magnetic resonance imaging (MRI) confirmed these effects in the transient model, in that infarct volume observed using apparent diffusion coefficient (ADC) maps was significantly smaller after 24 h in the ACEA 1021-treated rats compared with Tris-treated controls. Furthermore, the increase in perfusion signal intensity after reperfusion was more pronounced in the ACEA 1021-treated rats than in controls. In Fisher 344 rats with permanent occlusion of the middle cerebral artery, ACEA 1021 induced a dose-related decrease in infarct volume, which was associated with an improvement in neurological outcome as measured by the rope suspension procedure. Administration of the same dose regimen, as above, in Fisher rats with permanent middle cerebral artery occlusion reduced infarct volume by 68%. This dose was as effective when administration was delayed for 2 h. In mice with permanent middle cerebral artery occlusion, ACEA 1021 (5 mg/kg, i.v., 5 min after occlusion; 30 mg/kg, s.c., 1 and 4 h post-middle cerebral artery occlusion) decreased infarct size by 42%. The consistent anti-ischemic effects of ACEA 1021 make it a valuable compound for exploratory stroke research.

Junctional complexes of the blood-brain barrier: permeability changes in neuroinflammation.

A wide range of central nervous system (CNS) disorders include neuroinflammatory events that perturb blood-brain barrier (BBB) integrity. Mechanisms by which the BBB responds to physiological and pathological stimuli involve signaling systems in the tight and adherens junctions of the cerebral endothelium. In this review, we examine the molecular composition and regulatory mediators that control BBB permeability and assess how these mediators may be dysregulated in stroke, multiple sclerosis, brain tumors, and meningioencephalitis. An understanding of these molecular substrates in BBB regulation may lead to new approaches for enhancing CNS drug delivery and ameliorating brain edema after injury and inflammation.