Abstract
The role of Histamine H3 receptors (H3Rs) in memory, and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer disease (AD) is well-accepted. For that reason, the procognitive effects of the H3R antagonist DL77 on cognitive impairments induced with MK801 were tested in an inhibitory passive avoidance paradigm (PAP) and novel object recognition (NOR) task in adult male rats, using donepezil (DOZ) as a standard drug. Acute systemic pretreatment with DL77 (2.5, 5, and 10 mg/kg, i.p.) significantly ameliorated memory deficits induced with MK801 in PAP (all P < 0.05, n = 7). The ameliorative effect of most promising dose of DL77 (5 mg/kg, i.p.) was reversed when rats were co-injected with the H3R agonist R-(α)-methylhistamine (RAMH, 10 mg/kg, i.p.) (p = 0.701 for MK801-amnesic group vs. MK801+DL77+RAMH group, n = 6). In the NOR paradigm, DL77 (5 mg/kg, i.p.) counteracted long-term memory (LTM) deficits induced with MK801 (P < 0.05, n = 6–8), and the DL77-provided effect was similar to that of DOZ (p = 0.788, n = 6–8), and was reversed when rats were co-injected with RAMH (10 mg/kg, i.p.) (p = 0.877, n = 6, as compared to the (MK801)-amnesic group). However, DL77 (5 mg/kg, i.p.) did not alter short-term memory (STM) impairment in NOR test (p = 0.772, n = 6–8, as compared to (MK801)-amnesic group). Moreover, DL77 (5 mg/kg) failed to modify anxiety and locomotor behaviors of animals innate to elevated-plus maze (EPM) (p = 0.67 for percentage of time spent exploring the open arms, p = 0.52 for number of entries into the open arms, p = 0.76 for percentage of entries into the open arms, and p = 0.73 number of closed arm entries as compared to saline-treated groups, all n = 6), demonstrating that the procognitive effects observed in PAP or NOR tests were unconnected to alterations in emotions or in natural locomotion of tested animals. These results signify the potential involvement of H3Rs in modulating neurotransmitters related to neurodegenerative disorders, e.g., AD.
Highlights
Alzheimer’s disease (AD) is a life long-lasting brain disorder that is considered by its cognitive deficits, memory impairment, and dementia (Khunnawutmanotham et al, 2016; Shaik et al, 2016)
Among a wide range of H3R antagonists investigated so far, H3R antagonists ABT-239 and A-431404 were found to ameliorate cognitive deficits induced by ketamine and MK-801 in rodents, demonstrating enhanced procognitive effects of these compounds compared to standard drugs, e.g., Abbreviations: AD, Alzheimer disease; H3Rs, histamine H3 receptors; R-(α)-methylhistamine dihydrochloride (RAMH), R-(α)-methyl-histamine; DOZ, donepezil; MK801, dizocilpine; PAP, passive avoidance paradigm; STL, step-through latency; NOR, novel object recognition; STM, short-term memory; LTM, long-term memory; elevated-plus maze (EPM), elevated plus maze; p.o., per oral; i.p., intraperitoneal
In the current study and as a continuation of our research efforts, the procognitive effects of the nonimidazole H3R antagonist, namely DL77 [1-(3-(4-tertpentylphenoxy)propyl)piperidine dihydrogenoxalate], with high in vitro selectivity to human H3R, high antagonist affinity in the subnanomolar concentration range and a pKi-value of 8.03, and high H3R antagonist in vivo potency with an ED50 value of 2.1 ± 0.2 mg/kg, per oral (p.o.) (Łazewska et al, 2006) has been explored on its procognitive effects on memory deficits induced with MK801 in PAP and NOR paradigms in adult male rats applying DOZ as a reference drug
Summary
Alzheimer’s disease (AD) is a life long-lasting brain disorder that is considered by its cognitive deficits, memory impairment, and dementia (Khunnawutmanotham et al, 2016; Shaik et al, 2016). Brain histamine is an established neurotransmitter in the central nervous system (CNS) (Arrang et al, 1983, 1985, 1987a,b, 1988, 2007; Schwartz et al, 1986), exerting its biological activities through interaction with four histamine receptor (HR) subtypes (H1-H4R) that belong to the family of G-protein coupled receptors (Schneider and Seifert, 2009; Panula et al, 2015). Among a wide range of H3R antagonists investigated so far, H3R antagonists ABT-239 and A-431404 were found to ameliorate cognitive deficits induced by ketamine and MK-801 in rodents, demonstrating enhanced procognitive effects of these compounds compared to standard drugs, e.g., Abbreviations: AD, Alzheimer disease; H3Rs, histamine H3 receptors; RAMH, R-(α)-methyl-histamine; DOZ, donepezil; MK801, dizocilpine; PAP, passive avoidance paradigm; STL, step-through latency; NOR, novel object recognition; STM, short-term memory; LTM, long-term memory; EPM, elevated plus maze; p.o., per oral; i.p., intraperitoneal
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