Bernd Elger

Glutamate AMPA receptors change in motor neurons of SOD1G93A transgenic mice and their inhibition by a noncompetitive antagonist ameliorates the progression of amytrophic lateral sclerosis-like disease

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder involving the selective degeneration of motor neurons. In a small proportion of patients, ALS is caused by mutations in copper/zinc superoxide dismutase (SOD1), and mice overexpressing SOD1G93A mutant develop a syndrome that closely resembles the human disease. Excitotoxicity mediated by glutamate AMPA receptors has been suggested to be implicated in the selective susceptibility of motor neurons occurring in ALS. In SOD1G93A mice, we found that levels of GluR2 AMPA subunit, which plays a pivotal role in the maintenance of calcium impermeability of AMPA receptors, are decreased in spinal motor neurons before symptom onset in concomitance with a modest increase of GluR3 expression, a calcium‐permeable AMPA subunit. This effect can result in a higher number of calcium‐permeable AMPA receptors on motor neurons of SOD1G93A mice, predisposing these cells to be injured by AMPA‐mediated glutamate firing. In support of this, we showed that treatment with a new noncompetitive AMPA antagonist, ZK 187638, partially protected motor neurons, improved motor function, and prolonged the survival of SOD1G93A mice.

Optimized synthesis of AMPA receptor antagonist ZK 187638 and neurobehavioral activity in a mouse model of neuronal ceroid lipofuscinosis.

Previous structure–activity relationship studies in the search for a potent, noncompetitive α‐amino‐3‐(3‐hydroxy‐5‐methyl‐4‐isoxazolyl)propionic acid (AMPA) receptor antagonist led to 2,3‐dimethyl‐6‐phenyl‐12H‐[1,3]dioxolo[4,5‐h]imidazo[1,2‐c][2,3]benzodiazepine (ZK 187638). However, the first synthesis had some drawbacks regarding reagents, processes, and overall yield, which furthermore decreased when the synthesis was scaled up. Therefore, we now report a new synthetic route for this compound which requires fewer steps and is suited for large‐scale production. This compound significantly relieved the symptoms of neuromuscular deficit in mnd mice, a model of neuronal ceroid lipofuscinosis with motor neuron dysfunction. After oral administration, the concentrations of the compound in the brain and spinal cord were about threefold higher than those in the plasma. In summary, this novel AMPA antagonist is accessible through an optimized synthetic route, has good neurobehavioral activity, oral bioavailability, and favorable brain penetration. This opens new possibilities for the treatment of devastating neurological diseases that are mediated by the AMPA receptor.

Extended therapeutic time window after focal cerebral ischemia by non-competitive inhibition of AMPA receptors.

In acute stroke, the therapeutic time window is a critical factor which may have contributed to the failure of several phase III clinical trials with so-called neuroprotective agents. Since cerebral glutamate levels are elevated for many hours in progressing stroke, we investigated the novel AMPA glutamate receptor antagonist ZK 187638 in rodent models of stroke using up to 12 h delays in the start of therapy after permanent occlusion of the middle cerebral artery (MCA). In rats, ZK 187638 reduced total infarct volume by 43% and 33% when therapy was started immediately or with a delay of 6 h, respectively, but no effect was observed after a 12 h delay. Dose-dependent decreases of total infarct volume (up to 42%) were measured in mice given the first injection of ZK 187638 6 h after permanent MCA occlusion. In conclusion, the AMPA receptor antagonist ZK 187638 has a therapeutic time window of at least 6 h after permanent focal cerebral ischemia in rodents.