dizocilpine-maleate and pitolisant

Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33.9nM and hH3R antagonism with Ki of 76.2nM, respectively. In the present study, the effects of UW-MD-71 (1.25-5mg/kg, i.p.) on acquisition, consolidation, and retrieval in a one-trial inhibitory avoidance task in male rats were investigated applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. Furthermore, the effects of UW-MD-71 on memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were tested. Our results indicate that administration of UW-MD-71 before the test session dose-dependently increased performance and enhanced procognitive effect on retrieval. However neither pre- nor post-training acute systemic administration of UW-MD-71 facilitated acquisition or consolidation. More importantly, UW-MD-71 (2.5mg/kg, i.p.) ameliorated the DIZ-induced amnesic effects. Furthermore, the procognitive activity of UW-MD-71 in retrieval was completely reversed and partly abrogated in DIZ-induced amnesia when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL), but not with the CNS penetrant H1R antagonist pyrilamine (PYR). These results demonstrate the procognitive effects of UW-MD-71 in two in vivo memory models, and are to our knowledge the first demonstration in vivo that a potent dual-acting H3R antagonist and AChEI is effective in improving retrieval processes in the one-trial inhibitory avoidance task and provide evidence to such compounds to treat cognitive disorders.

Topics: Animals; Avoidance Learning; Benzothiazoles; Cholinesterase Inhibitors; Disease Models, Animal; Dizocilpine Maleate; Donepezil; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Histamine H3 Antagonists; Indans; Male; Memory; Memory Disorders; Nootropic Agents; Phenoxypropanolamines; Piperidines; Pyrilamine; Pyrroles; Quinazolines; Random Allocation; Rats, Wistar; Receptors, Histamine H3

Numerous studies have demonstrated that brain histamine plays a crucial role in learning and memory and histamine H3 receptor inverse agonists (H3R inverse agonists) have been proposed to treat cognitive disorders. Pitolisant (BF2.649, 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride) was the first H3R inverse agonist that has been tested in human trials and is well tolerated. The present study investigated whether Pitolisant (0.625-20mg/kg, i.p.) improves consolidation and reconsolidation processes in the fear conditioning task in female C57BL/6J mice. We also tested whether Pitolisant reverses memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (MK-801). Our results indicate that post-training systemic injections of Pitolisant facilitated consolidation of contextual fear memory and reversed amnesia induced by an i.p. injection of 0.12 mg/kg dizocilpine. In addition, none of the doses of Pitolisant we have tested after reactivation (reexposure to the context in which training took place 48 h earlier) affected reconsolidation, whereas dizocilpine disrupted it. However, Pitolisant was able to reverse the deficit in reconsolidation induced by 0.12 mg/kg dizocilpine. The present results are the first demonstration that Pitolisant is effective in improving consolidation processes in the fear condition task and add further evidence to its potential for treating cognitive disorders.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fear; Female; Histamine Agonists; Memory; Mice; Mice, Inbred C57BL; N-Methylaspartate; Piperidines

H(3)-receptor inverse agonists raise a great interest as innovative therapeutics in several central disorders. Whereas their procognitive properties are well established, their antipsychotic-like properties are still debated.. We further explored the effect of maximal doses (3-10 mg/kg) of ciproxifan, BF2.649, and ABT-239, three selective H(3)-receptor inverse agonists, on deficits of prepulse inhibition (PPI) induced by apomorphine, MK-801, and phencyclidine (PCP). Their effect was also investigated on stereotypies induced by apomorphine and methamphetamine.. Ciproxifan, BF2.649, and ABT-239 did not reverse the PPI impairment produced by apomorphine (0.5 mg/kg, subcutaneous) in rats. Ciproxifan and BF2.649 did not reverse the impairment induced in mice by MK-801 (0.3 mg/kg). Ciproxifan and BF2.649 also failed to reverse the disruption induced in mice by PCP (5-10 mg/kg). Low to moderate doses of haloperidol (0.1-0.4 mg/kg, intraperitoneal), alone or co-administered with BF2.649, did not reverse MK-801-induced PPI disruption. A high dose (1 mg/kg) of haloperidol partially reversed the MK-801-induced deficit and BF2.649 tended to increase this effect, although nonsignificantly. Whereas stereotypies induced in mice by apomorphine and methamphetamine were totally suppressed by haloperidol, the decrease induced by ciproxifan was partial against apomorphine and very low, if any, against methamphetamine.. Their total absence of effect in several validated animal models of the disease does not support antipsychotic properties of H(3)-receptor inverse agonists. However, their positive effects previously reported in behavioral tasks addressing learning, attention, and memory maintain the interest of H(3)-receptor inverse agonists for the treatment of cognitive symptoms of schizophrenia as adjunctive medications.

Topics: Animals; Antipsychotic Agents; Apomorphine; Benzofurans; Dizocilpine Maleate; Drug Inverse Agonism; Haloperidol; Histamine Antagonists; Imidazoles; Inhibition, Psychological; Male; Methamphetamine; Mice; Phencyclidine; Piperidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Reflex, Startle; Stereotyped Behavior