ro4368554 and Cognition-Disorders

Alzheimer's disease (AD) is one of the most frequent causes of death and disability worldwide and has a significant clinical and socioeconomic impact. In the search for novel therapeutic strategies, serotonin 5-HT6 receptor (5-HT6R) has been proposed as a promising drug target for cognition enhancement in AD. This manuscript reviews the compelling evidence for the implication of this receptor in learning and memory processes. We have summarized the current status of the medicinal chemistry of 5-HT6R antagonists and the encouraging preclinical findings that demonstrate their significant procognitive behavioral effects in a number of learning paradigms, probably acting through modulation of multiple neurotransmitter systems and signaling pathways. The results of the ongoing clinical trials are eagerly awaited to shed some light on the validation of 5-HT6R antagonists as a new drug class for the treatment of symptomatic cognitive impairment in AD, either as stand-alone therapy or in combination with established agents.

Topics: Alzheimer Disease; Binding Sites; Clinical Trials as Topic; Cognition Disorders; Humans; Models, Molecular; Molecular Structure; Protein Structure, Tertiary; Receptors, Serotonin; Serotonin Antagonists

Malfunction of the serotonin system may contribute to memory deficits during aging. We evaluated the 5-HT(6) antagonist RO4368554 in two models of learning and memory in aged rats. Male rats (18 months) were assigned to two groups of equal cognitive performance. After 2 weeks of 5-HT(6) antagonist RO4368554 (5 mg/kg, i.p.) treatment, rats showed significant improvement in object recognition and social discrimination compared with rats given chronic vehicle. Brains from these animals were examined for changes in plasticity-associated proteins Ki-67 and PCNA. No differences were seen between groups in any of these markers. We also measured mRNA expression of 5-HT(6), along with 5-HT(1A), 5-HT(1B), and tryptophan hydroxylase-2 mRNAs in 4-month-old and 24-month-old F344 rats. Decreases in 5-HT(1B) expression were observed in several forebrain regions in the old rats. These results demonstrate that 5-HT(6) and 5-HT(1B) receptors are potential targets for treatment of age-related memory disorders.

Topics: Aging; Animals; Brain; Cognition Disorders; Indoles; Ki-67 Antigen; Male; Memory Disorders; Neuronal Plasticity; Piperazines; Proliferating Cell Nuclear Antigen; Rats; Rats, Inbred F344; Rats, Long-Evans; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; RNA, Messenger; Serotonin; Serotonin Antagonists; Tryptophan Hydroxylase