E169

The role of histamine H3 receptors (H3Rs) in memory and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer's disease (AD), is well-accepted. Therefore, the procognitive effects of acute systemic administration of H3R antagonist E169 (2.5-10 mg/kg, i.p.) on MK801-induced amnesia in C57BL/6J mice using the novel object recognition test (NORT) were evaluated. E169 (5 mg) provided a significant memory-improving effect on MK801-induced short- and long-term memory impairments in NORT. The E169 (5 mg)-provided effects were comparable to those observed with the reference phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and were abrogated with the H3R agonist (R)-α-methylhistamine (RAMH). Additionally, our results demonstrate that E169 ameliorated MK801-induced memory deficits by antagonism of H3Rs and by modulation of the level of disturbance in the expression of PI3K, Akt, and GSK-3β proteins, signifying that E169 mitigated the Akt-mTOR signaling pathway in the hippocampus of tested mice. Moreover, the results observed revealed that E169 (2.5-10 mg/kg, i.p.) did not alter anxiety levels and locomotor activity of animals in open field tests, demonstrating that performances improved following acute systemic administration with E169 in NORT are unrelated to changes in emotional response or in spontaneous locomotor activity. In summary, these obtained results suggest the potential of H3R antagonists such as E169, with good in silico physicochemical properties and stable retained key interactions in docking studies at H3R, in simultaneously modulating disturbed brain neurotransmitters and the imbalanced Akt-mTOR signaling pathway related to neurodegenerative disorders, e.g., AD.

Enaminones are a novel group of compounds that have been shown to possess anticonvulsant activity in in vivo animal models of seizures. The cellular mechanism by which these compounds produce their anticonvulsant effects is not yet known. This study examined the effects of enaminones on excitatory synaptic transmission.We studied the effects of 3‐(4′‐chlorophenyl)aminocyclohex‐2‐enone (E118), methyl 4‐(4′‐bromophenyl)aminocyclohex‐3‐en‐6‐methyl‐2‐oxo‐1‐oate (E139) and ethyl 4‐(4′‐hydroxyphenyl)aminocyclohex‐3‐en‐6‐methyl‐2‐oxo‐1‐oate (E169) on isolated evoked, glutamate‐mediated excitatory synaptic responses by recording whole‐cell currents and potentials in cells of the nucleus accumbens (NAc) contained in forebrain slices.The anticonvulsant enaminones (E118 and E139), but not E169, depressed NMDA and non‐NMDA receptor‐mediated synaptic responses. The inhibition of the non‐NMDA response was concentration‐dependent (1.0–100 μM) with a maximal depression of ∼−30%. E118 and E139 had similar potencies (EC50=3.0 and 3.5 μM, respectively) in depressing this response but E139 was more efficacious (Emax=−31.3±3.8%) than E118 (Emax=−22.6±1.6%).The excitatory postsynaptic current (EPSC) depression caused by 10 μM E139 (−27.7±3.8%) was blocked by 1 μM CGP55845 (6.3±8.1%), a potent GABAB receptor antagonist.Pretreatment of slices with γ‐vinylGABA and 1‐(2‐(((diphenylmethylene)imino)oxy)ethyl)‐1,2,5,6‐tetrahydro‐3‐pyridine‐carboxylic acid (NO‐711), an irreversible GABA transaminase (GABA‐T) inhibitor and a GABA reuptake blocker, respectively, like the anticonvulsant enaminones, also caused a depression of the evoked EPSC (−38.1±14.1 and −24.1±8.9%, respectively). In the presence of these compounds, E139 did not cause a further depression of the EPSC. Our data suggest that anticonvulsant enaminones cause EPSC depression by enhancing extracellular GABA levels possibly through the inhibition of either GABA reuptake or GABA‐T enzyme, or both.British Journal of Pharmacology (2005) 145, 945–953. doi:10.1038/sj.bjp.0706250