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The cannabinoid CB 2 receptor agonist AM 1241 enhances neurogenesis in GFAP / G p120 transgenic mice displaying deficits in neurogenesis
Author(s) -
Avraham Hava Karsenty,
Jiang Shuxian,
Fu Yigong,
Rockenstein Edward,
Makriyannis Alexandros,
Zvonok Alexander,
Masliah Eliezer,
Avraham Shalom
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12478
Subject(s) - neurogenesis , doublecortin , gliogenesis , biology , neural stem cell , astrogliosis , glial fibrillary acidic protein , neuroblast , subgranular zone , microbiology and biotechnology , immunology , hippocampal formation , stem cell , endocrinology , dentate gyrus , subventricular zone , immunohistochemistry , central nervous system
Background and Purpose HIV ‐1 glycoprotein G p120 induces apoptosis in rodent and human neurons in vitro and in vivo. HIV ‐1/ G p120 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 )/ G p120 transgenic ( T g) mice. As cannabinoids exert neuroprotective effects in several model systems, we examined the protective effects of the CB 2 receptor agonist AM 1241 on G p120‐mediated insults on neurogenesis. Experimental Approach We assessed the effects of AM 1241 on survival and apoptosis in cultures of human and murine NPCs with immunohistochemical and TUNEL techniques. Neurogenesis in the hippocampus of GFAP / G p120 transgenic mice in vivo was also assessed by immunohistochemistry. Key Results AM 1241 inhibited in vitro G p120‐mediated neurotoxicity and apoptosis of primary human and murine NPCs and increased their survival. AM 1241 also promoted differentiation of NPCs to neuronal cells. While GFAP / G p120 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 AM 1241 to GFAP / G p120 T g 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 / G p120 T g mice treated with AM 1241, compared with those treated with vehicle. Conclusions and Implications The CB 2 receptor agonist rescued impaired neurogenesis caused by HIV ‐1/ G p120 insult. Thus, CB 2 receptor agonists may act as neuroprotective agents, restoring impaired neurogenesis in patients with HAD .