Lamotrigine (3,5-diamino-6-(dichlorophenol)-1,2,4-triazine) is a phenyltriazine derivative that blocks voltage-gated Na⁺ channels and inhibits the ischaemia-induced release of glutamate. It is a commercially available, orally administered anticonvulsant with few side effects, although rashes and cases of Stevens-Johnson syndrome have been reported. (Bourgeois 1998, Dunn et al. 1999)

Riluzole (2-amino-6-trigluoromethoxy benzothiazole) is a voltage-gated Na⁺ channel blocker that is also used clinically in cases of neurodegenerative diseases. It prevented ischaemic spinal cord injury in a rabbit model (Lang-Lazdunski et al. 1999), in another experiment animals treated with it had a better histopathological outcome after cardiac arrest. (Kanthasamy et al. 1999)

Lubeluzole, a Na⁺ channel blocker that can inhibit the release of glutamate from ischaemic neurons, reducing postsynaptic excitotoxicity, may also inhibit postsynaptic nitric oxide synthetase activity. It has been shown in a rat model to improve the structural outcome for brain cells after global cerebral ischaemia. (Haseldonckx et al. 1997)

Lifarizine is a similar substance that was found to be a promising neuroprotectant in an experimental setting (Brown et al. 1995), but clinical trials were discontinued on account of cardiac side effects such as hypotension and arrhythmia. (Squire et al. 1995)

The voltage-dependent Na⁺ channel antagonist BW619C87 [4-amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl) pyrimidine]; has proved to a potent neuroprotectant, reducing the volume of hemispheric ischaemic damage by 51% at a dose of 50 mg/kg in a rat model. (Kawaguchi et al. 1999)

Non-competitive NMDA receptor antagonists. In order to reach its binding site, a non-competitive NMDA receptor antagonist requires an ion channel to be opened up and the voltage-dependent Mg²⁺ block to be released by postsynaptic membrane depolarization.

NPS-1506 is a non-competitive NMDA receptor antagonist with a moderate affinity to its receptor. It was found to be neuroprotective in a rodent model for ischaemic stroke, haemorrhagic stroke and head trauma, being less neurotoxic than MK-801. (Mueller et al. 1999)

Dextromethorphan and its analogue AHN649 are relatively selective, low-affinity NMDA antagonists, and have been shown to have neuroprotective efficacy in a rat model utilizing temporal intraluminal filament occlusion of the middle cerebral artery. (Britton et al. 1997, Tortella et al. 1999)

Aptiganel (CNS 1102) is a selective, non-competitive antagonist that acts on the ion channel associated with the NMDA receptor and has been shown to be neuroprotective in neonatal lambs after HCA. (Bokesch et al. 1997)

Remacemide hydrochloride and its principal active desglycinyl metabolite are low-affinity non-competitive NMDA receptor antagonists. Remacemide hydrochloride was shown to be neuroprotective in an animal model of hypoxia and ischaemic stroke, and overall postoperative neurological recovery in a clinical prospective study of 171 patients undergoing aortocoronary bypass grafting (CABG) with CPB was more favourable in the remacemide group than in the controls. (Arrowsmith et al. 1998)

Glycine site antagonists. Glycine, a major inhibitory neurotransmitter in the spinal cord and brainstem of vertebrates, is collected in the synaptic vesicles via a proton-coupled transport system and is released into the synaptic cleft after depolarization of the presynaptic terminal. It can participate in excitatory neurotransmission by modulating the activity of the NMDA subtype of the glutamate receptor.

7-Chlorokynuretic acid and its derivatives ACEA-1021 (Licostinel), ACEA-1031 and ACEA-1416 have also been found to reduce infarct volume in focal ischaemia models (Warner et al. 1995). Licostinel may be a safer and better tolerated neuroprotective agent than many of the previously evaluated NMDA antagonists. (Albers et al. 1999)

Felbamate, a novel anticonvulsant that binds to the glycine site of the NMDA receptor, has been shown to have neuroprotective properties in vitro and in vivo. In a gerbil model of global ischaemia, felbamate given after carotid occlusion prevented delayed apoptosis, but the doses required to reach this effect were higher than those used for anticonvulsant treatment. (Wasterlain et al. 1996)

Monosialogangliosides play important roles in the physiological pathways of the nervous system, particularly in the brain.

GM1 has also been shown to reduce cerebral injury following 2 hours of HCA at 18°C. In an experiment with adult dogs, a better behavioural outcome and less neuronal injury was seen in dogs pretreated with GM1 than in the controls. (Redmond et al. 1993)

Calcium channel blockers may reduce Ca²⁺ influx into cells after the activation of EAA receptors, and they also inhibit vasoconstriction after ischaemic insult (Lipton and Rosenberg 1994). Calcium antagonists have been shown to improve the neurological outcome after aneurysmal subarchnoidal haemorrhage.

NO has been shown to mediate glutamate excitotoxicity, and the therapeutic potential of NOS inhibitors have been emphasized. (Barth et al. 1997)

ARL17477, a selective NOS inhibitor, also provided some neuroprotection in a gerbil model, but the combination of MK-801 with ARL17477 provided 21% or 44% higher protection than either alone, indicating that several pathways contribute to ischaemic cell death and several agents targeting different points in the biochemical cascade may be of benefit (Hicks et al. 1999).

One possibility for pharmacologically targeting a "downstream" event in the cascade is to inhibit activated calpain. The CNS-penetrating calpain inhibitor MDL 28,170 can reduce infarct volume in rodents (Markgraf et al. 1998), as also can another inhibitor Cbz-Val-Phe-H. (Hong et al. 1994)

Gelsolin expression at normal levels protects the brain from acute ischaemic injury with its ability to stabilize CA²⁺ influx. Cytochalacin D is a partial gelsolin analogue and can reduce ischaemic injury, although this can lead to apoptosis. (Endres et al. 1999)