hemopressin and Alzheimer-Disease

Cannabinoid receptors (CBRs) are part of the endocannabinoid system, which is involved in various physiological processes such as nociception, inflammation, appetite, stress, and emotion regulation. Many studies have linked the endocannabinoid system to neuroinflammatory and neurodegenerative disorders such as Parkinson's disease, Huntington's chorea, Alzheimer's disease, and multiple sclerosis. Hemopressin [Hp; a fragment of the hemoglobin α1 chain (95-103 amino acids)] and related peptides [VD-Hpα and RVD-Hpα] are peptides that bind to CBRs. Hp acts as an inverse agonist to CB

Topics: Alzheimer Disease; Animals; Cannabinoid Receptor Agonists; Cannabinoids; Hemoglobins; Humans; Peptide Fragments; Receptors, Cannabinoid

Dysfunction in the cholinergic system and oxidative stress are closely related and play roles in Alzheimer's disease (AD). Scopolamine (Scop), which is commonly used to induce cholinergic system damage in cells and animals, also evokes oxidative stress. Our previous study indicated that the peptide (m) RVD-hemopressin (RVD) reversed the memory-impairing effect of Scop in mice by activating cannabinoid receptor 1 (CBR1), but the mechanism was unclear. In this study, we found that RVD inhibited the oxidative stress, apoptosis, decreased cell viability and downregulation of synapse-associated proteins induced by Scop in HT22 cells. The effect was associated with the BDNF/TrkB/Akt pathway, and the effects of RVD outlined above could be blocked by an antagonist of CBR1. These results suggest that RVD may be a potential drug candidate for disorders associated with damage to the cholinergic system and oxidative stress, such as AD.

Topics: Alzheimer Disease; Animals; Apoptosis; Brain-Derived Neurotrophic Factor; Cholinergic Agents; Mice; Oxidative Stress; Proto-Oncogene Proteins c-akt; Scopolamine

The cannabinoid system plays an important role in memory processes, many studies have indicated that cannabinoid receptor ligands have ability to modulate memory in rodents. A nonapeptide hemopressin (Hp) derived from rat brain, acts as a peptide antagonist or selective inverse peptide agonist of cannabinoid 1 (CB1) receptor. N-terminally extended forms of Hp isolated from mouse brain, (m)RVD-hemopressin(α) (RVD) and (m)VD-hemopressin(α) (VD) also bind CB1 receptor, however, as peptide agonists. Here, we investigated the roles of Hp, RVD, and VD on memory in mice using novel object recognition (NOR) and object location recognition (OLR) tasks. In normal young mice, intracerebroventricular (i.c.v.) infusion of Hp before training not only improved memory formation, but also prolonged memory retention in the tasks, these effects could be inhibited by RVD or VD at the same dose and intraperitoneal (i.p.) injection of a small molecule agonist of CB1 receptor WIN55, 212-2 15min before administration of Hp inhibited the memory-improving effect of Hp. In addition, under the same experimental conditions, i.c.v. RVD or VD displayed memory-impairing effects, which could be prevented by Hp (i.c.v.) or AM251 (i.p.), a small molecule antagonist of CB1 receptor. Infusion of amyloid-β (1-42) (Aβ1-42) 14days before training resulted in impairment of memory in mice which could be used as animal model of Alzheimer's disease (AD). In these mice, RVD or VD (i.c.v.) reversed the memory impairment induced by Aβ1-42, and the effects of RVD and VD could be suppressed by Hp (i.c.v.) or AM251 (2mg/kg, i.p.). Separate administration of Hp had no effect in Aβ1-42-treated mice. The above results suggested that Hp, RVD and VD, as CB1 receptor peptide ligands, may be potential drugs to treatment of the memory deficit-involving disease, just as AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Benzoxazines; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Disease Models, Animal; Hemoglobins; Infusions, Intraventricular; Male; Memory Disorders; Mice; Morpholines; Naphthalenes; Oligopeptides; Peptide Fragments; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Recognition, Psychology