| Studies were carried out with the goal of determining the neurochemical properties and neuroprotective potential of several novel gamma-aminobutyric acid (GABA)-elevating agents derived from phenylethylidenehydrazine (PEH). Three agents, 4-fluoro-PEH (FPEH), 4-methyl-PEH (MPEH) and 4-methoxy-PEH (MeOPEH) were examined with respect to their effects (acute and chronic) on gerbil brain amino acid levels, GABA-transaminase (GABA-T), alanine-transaminase (ala-T), monoamine oxidase (MAO), cytochrome P450 (CYP) enzyme-catalyzed metabolism and core temperature as well as their neuroprotective efficacies in gerbil hippocampus (transient forebrain ischemia) and rat hippocampus (DSP-4 toxicity). Acute administration of the PEH analogues was associated with significant inhibition of brain GABA-T and ala-T, increases in brain GABA and alanine levels and transient reduction of core temperature. Phenelzine (PLZ), which inhibits monoamine oxidase (MAO) in addition to GABA-T, caused a more marked reduction in body temperature in the gerbils than did PEH or its three analogues. FPEH and PEH were further examined for their effects on GABA-T and ala-T in vitro and caused dose-dependent inhibition. FPEH was also studied for its effects on MAO-A and -B ex vivo and, in contrast to PLZ, produced only weak inhibition of MAO. FPEH, in contrast to MePEH and MeOPEH, caused a decrease in brain levels of glutamate (acutely and chronically) and glutamine (acutely). All of the analogues interfered with CYP-mediated metabolism, with the effects generally being more potent on CYPs 1A2, 2B6 and 2C19 than on 2D6 and 3A4.; Despite having similar effects on the enzymes GABA-T and ala-T as well as on brain GABA and alanine levels in acute studies, the PEH analogues (at 30 mg/kg i.p.) exhibited differing neuroprotective efficacies, with FPEH being the only one of the analogues to exhibit neuroprotective activity in vivo when administered three hours post-stroke and then once daily for 7 days in gerbils. FPEH was also more effective than MePEH and MeOPEH at reducing glutamate levels, which may account for its neuroprotective effect. The PEH analogues showed little or no activity in the DSP-4-induced hippocampal depletion model in the rat. |
