PNQX

PNQX (9-methyl-amino-6-nitro-hexahydro-benzo(F)quinoxalinedione) is a selective AMPA antagonist with demonstrated neuroprotective effects in focal ischemia in rats. Here we report corresponding effects in mouse hippocampal slice cultures subjected to oxygen and glucose deprivation (OGD) and in transient global cerebral ischemia in gerbils. For in vitro studies, hippocampal slice cultures derived from 7-day-old mice and grown for 14 days, were submersed in oxygen-glucose deprived medium for 30 min and exposed to PNQX for 24 h, starting together with OGD, immediately after OGD, or 2 h after OGD. For comparison, other cultures were exposed to the NMDA antagonist MK-801 using the same protocol. Both PNQX and MK-801 displayed significant neuroprotective effects in all hippocampal subfields when present during and after OGD. When added just after OGD, only PNQX retained some neuroprotective effect. When added 2 h after OGD neither PNQX nor MK-801 had an effect. Transient global cerebral ischemia was induced in Mongolian gerbils by occlusion of both common carotid arteries for 4.5 min, with PNQX (10 mg/kg) being injected i.p. 30, 60 and 90 min after the insult. Subsequent analysis of brain sections stained for the neurodegeneration marker Fluoro-Jade B and immunostained for the astroglial marker glial fibrillary acidic protein revealed a significant PNQX-induced decrease in neuronal cell death and astroglial activation. We conclude that, PNQX provided neuroprotection against both global cerebral ischemia in gerbils in vivo and oxygen-glucose deprivation in mouse hippocampal slice cultures.

Sciatic nerve injury in neonatal rats results in significant reduction in the number of surviving motoneurons and impairs muscle development. We examined the possible neuroprotective effects of daily in vivo administration of 1,4,7,8,9,10-hexahydro-9-methyl-6-nitropyrido[3,4-f]quinoxaline-2,3-dione (PNQX), an AMPA/kainate receptor antagonist, on sciatic nerve injured rats, during the period of plasticity of the rat nervous system. Furthermore, we investigated the effect of PNQX on muscle properties impaired by nerve crush. At the second postnatal day, the sciatic nerve of the rat left hind limb was crushed. Twenty-four rats were subsequently treated with PNQX and an equal number of rats, as control group, were treated with saline. PNQX was injected subcutaneously once daily (14 mg kg(-1) body weight). Treatment continued until the rats were 14 days old. Measurements were then carried out to assess the contractile properties of the extensor digitorum longus (EDL), a fast-contracting muscle, and of the soleus muscle, a slow-contracting muscle, in four "age groups" of rats, each consisting of six PNQX-treated and six control animals: (a) postnatal day (P) 14, (b) postnatal day (P) 21, (c) postnatal day (P) 28 and (d) adult rats. The following parameters were recorded: number of motor units, muscle weight, maximal tetanic tension (TET 100), time to peak (TTP), half relaxation time (HRT), and fatigue index (FI). Improvement in motor unit survival after nerve injury was observed in all age groups administering PNQX. Also axotomy-induced impairment of muscle properties such as muscle weight, tension development, contraction and relaxation velocity was counteracted by injection of PNQX. The fatigue index was altered by axotomy and mostly normalized by treatment with this compound. AMPA/kainate receptor antagonists, with low toxicity, may serve in the future, as possible neuroprotective agents after acute neural injury or even as therapeutic agents in neurodegenerative diseases.