title: ACEA (a highly selective cannabinoid CB1 receptor agonist) stimulates hippocampal neurogenesis in mice treated with antiepileptic drugs.
abstract: Hippocampal neurogenesis plays a very important role in learning and memory functions. In a search for best neurological drugs that protect neuronal cells and stimulate neurogenesis with no side effects, cannabinoids proved to be a strong group of substances having many beneficial properties. The aim of this study was to evaluate the impact of ACEA (arachidonyl-2'-chloroethylamide--a highly selective cannabinoid CB1 receptor agonist) combined with a classical antiepileptic drug sodium valproate (VPA) on neural precursor cells' proliferation and differentiation in the mouse brain. All experiments were performed on adolescent CB57/BL male mice injected i.p. with VPA (10mg/kg), ACEA (10mg/kg) and PMSF (30 mg/kg) (phenylmethylsulfonyl fluoride--a substance protecting ACEA against degradation by the fatty-acid amidohydrolase) for 10 days. Next an acute response of proliferating neural precursor cells to ACEA and VPA administration was evaluated with Ki-67 staining (Time point 1). Next, in order to determine whether acute changes translated into long-term alterations in neurogenesis, proliferating cells were labeled with 5-bromo-2deoxyuridine (BrdU) followed by confocal microscopy used to determine the percentage of BrdU-labeled cells that showed mature cell phenotypes (Time point 2). Results indicate that ACEA with PMSF significantly increase the total number of Ki-67-positive cells when compared to the control group. Moreover, ACEA in combination with VPA increased the number of Ki-67-positive cells, whereas VPA administered alone had no impact on proliferating cells' population. Accordingly, neurogenesis study results indicate that the combination of ACEA+PMSF administered alone and in combination with VPA considerably increases the total number of BrdU-positive cells in comparison to the control group while ACEA+PMSF alone and in combination with VPA increased total numbers of BrdU-positive cells, newly born neurons and astrocytes as compared to VPA group but not to the control group. VPA administered alone decreased the number of newly born neurons with no significant impact on neurogenesis. These data provide substantial evidence that VPA administered chronically slightly decreases the proliferation and differentiation of newly born cells while combination of VPA+ACEA significantly increases the level of newborn neurons in the dentate subgranular zone.
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, Poland. Electronic address: mandres@wp.pl.
authors.forename: Marta
authors.initials: M
authors.lastname: Andres-Mach
authors.affiliation: Department of Physiopathology, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Haratym-Maj
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, Poland.
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Zagaja
authors.affiliation: Department of Physiopathology, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, Poland; Department of Neurological Surgery, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Rola
authors.affiliation: Department of Clinical Immunology, Medical Univeristy of Lublin, Chodzki 4A, 20-090 Lublin, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Maj
authors.affiliation: Department of Child Neurology, Medical University of Lublin, Chodzki 2, 20-093 Lublin, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Chrościńska-Krawczyk
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, Poland; Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland.
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Luszczki
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D055495:Neurogenesis / Q000187:drug effects*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D001095:Arachidonic Acids; D019394:Ki-67 Antigen; D043884:Receptor, Cannabinoid, CB1; C119325:arachidonyl-2-chloroethylamide; D014635:Valproic Acid; D001973:Bromodeoxyuridine
keywords: ACEA; Hippocampal neurogenesis; Neural precursor cells; Valproic acid