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.

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%.

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.