The Histamine H3 Receptor Antagonist DL77 Ameliorates MK801-Induced Memory Deficits in Rats

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.

<p>Histamine H3 receptor antagonist E177 attenuates amnesia induced by dizocilpine without modulation of anxiety-like behaviors in rats</p>

“…11,12,44,45 The experiments were conducted in accordance with the previously published protocols. 11,12,33,[45][46][47][48][49][50][51] The test was conducted over 3 days (two consecutive training days, with the test performed on the third day). The animal was placed in the white compartment in front of the door for a 30-second habituation period at the beginning of the first training day, and then the door was routinely raised up.…”

“…Doses of all tested compounds were selected based on previously conducted experiments for several non-imidazole-based H3R antagonists tested in adult male rats (Figures 2 and 3). 33,52,53…”

“…The NOR task was used to assess both the short-term memory (STM) and long-term memory (LTM) recognition in male Wistar rats by using an open square black box (50×35×50 cm), as described previously. 33,45 The NOR task was conducted in the morning between 8:00 am and 12:00 pm. On the first day, two habituation sessions, separated by 1 hour, were conducted; each animal was allowed to habituate the box for 3 minutes and was then returned to its home cage and the box was cleaned.…”

“…16,17,25,27,28 Subsequently, various H3R antagonists, such as ABT-239 and A-431404, were shown to attenuate memory impairments induced by dizocilpine (DIZ) or ketamine in different animal species, and their procognitive effect was comparable with standard drugs, such as donepezil (DOZ), 29 which was suggestive of the potential use for H3R antagonists in the treatment of neurodegenerative diseases such as AD. 17,[30][31][32][33] Consequently, H3Rs appear to be a very attractive target for the design of new H3R antagonists suitable for the treatment of many neuropsychiatric diseases, including epilepsy, schizophrenia, and AD. 17,27,31,[34][35][36][37][38][39][40][41][42] Targeting H3Rs is not commonly employed for the treatment of AD, despite the previous indications about the memory-enhancing effects in neurodegenerative disorders.…”

Histamine H3 Receptor Antagonist Enhances Neurogenesis and Improves Chronic Cerebral Hypoperfusion-Induced Cognitive Impairments

“…Inhibition of H3R can protect against ischemic injury by enhancing autophagy (Yan et al, 2014). The H3R antagonist protects against traumatic brain injury (TBI) by regulating H1R (Liao et al, 2019), and also ameliorates the cognitive deficits induced by N-methyl-Daspartic acid receptor (NMDAR) antagonists like ketamine and MK-801 (Eissa et al, 2018). Inhibiting H3R also improves context discrimination task in aged mice (Guilloux et al, 2017).…”