title: The cannabinoid CB₂ receptor agonist AM1241 enhances neurogenesis in GFAP/Gp120 transgenic mice displaying deficits in neurogenesis.
abstract: OBJECTIVE
  HIV-1 glycoprotein Gp120 induces apoptosis in rodent and human neurons in vitro and in vivo. HIV-1/Gp120 is involved in the pathogenesis of HIV-associated dementia (HAD) and inhibits proliferation of adult neural progenitor cells (NPCs) in glial fibrillary acidic protein (GFAP)/Gp120 transgenic (Tg) mice. As cannabinoids exert neuroprotective effects in several model systems, we examined the protective effects of the CB₂ receptor agonist AM1241 on Gp120-mediated insults on neurogenesis.
  
  
  METHODS
  We assessed the effects of AM1241 on survival and apoptosis in cultures of human and murine NPCs with immunohistochemical and TUNEL techniques. Neurogenesis in the hippocampus of GFAP/Gp120 transgenic mice in vivo was also assessed by immunohistochemistry.
  
  
  RESULTS
  AM1241 inhibited in vitro Gp120-mediated neurotoxicity and apoptosis of primary human and murine NPCs and increased their survival. AM1241 also promoted differentiation of NPCs to neuronal cells. While GFAP/Gp120 Tg mice exhibited impaired neurogenesis, as indicated by reduction in BrdU⁺ cells and doublecortin⁺ (DCX⁺) cells, and a decrease in cells with proliferating cell nuclear antigen (PCNA), administration of AM1241 to GFAP/Gp120 Tg mice resulted in enhanced in vivo neurogenesis in the hippocampus as indicated by increase in neuroblasts, neuronal cells, BrdU⁺ cells and PCNA⁺ cells. Astrogliosis and gliogenesis were decreased in GFAP/Gp120 Tg mice treated with AM1241, compared with those treated with vehicle.
  
  
  CONCLUSIONS
  The CB₂ receptor agonist rescued impaired neurogenesis caused by HIV-1/Gp120 insult. Thus, CB₂ receptor agonists may act as neuroprotective agents, restoring impaired neurogenesis in patients with HAD.
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Hava Karsenty
authors.initials: HK
authors.lastname: Avraham
authors.forename: Shuxian
authors.initials: S
authors.lastname: Jiang
authors.forename: Yigong
authors.initials: Y
authors.lastname: Fu
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.forename: Alexander
authors.initials: A
authors.lastname: Zvonok
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Shalom
authors.initials: S
authors.lastname: Avraham
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002186:Cannabinoids / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000089662:Doublecortin Protein; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D015699:HIV Envelope Protein gp120 / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D061251:Primary Cell Culture; D060888:Real-Time Polymerase Chain Reaction; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000096:biosynthesis
chemical_list: C439263:AM 1241; D002186:Cannabinoids; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D005904:Glial Fibrillary Acidic Protein; D015699:HIV Envelope Protein gp120; D043885:Receptor, Cannabinoid, CB2
keywords: CB2 agonist; GFAP/Gp120 transgenic mice; HIV-1 Gp120 protein; neural progenitor cells; neurogenesis