The cannabinoid CB2 receptor agonist AM1241 enhances neurogenesis in GFAP/Gp120 transgenic mice displaying deficits in neurogenesis. (January 2014)

• Record Type: Journal Article
• Authors: Avraham, Hava Karsenty; Jiang, Shuxian; Fu, Yigong; Rockenstein, Edward; Makriyannis, Alexandros; Zvonok, Alexander; Masliah, Eliezer; Avraham, Shalom
• Is Part Of: British journal of pharmacology. Volume 171:Number 2(2014:Jan.)
• Page Start: 468
• Page End: 479
• Publication Date: 2014-01
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12478
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12478-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>HIV‐1 glycoprotein Gp120 induces apoptosis in rodent and human neurons <italic>in vitro</italic> and <italic>in vivo.</italic> 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 CB<sub>2</sub> receptor agonist AM1241 on Gp120‐mediated insults on neurogenesis.</p> </sec> <sec id="bph12478-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>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 <italic>in vivo</italic> was also assessed by immunohistochemistry.</p> </sec> <sec id="bph12478-sec-0003" sec-type="section"> <title>Key Results</title> <p>AM1241 inhibited <italic>in vitro</italic> 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<sup>+</sup> cells and doublecortin<sup>+</sup> (DCX<sup>+</sup>) cells, and a decrease in cells with proliferating cell nuclear antigen (PCNA), administration of AM1241 to GFAP/Gp120 Tg mice resulted in enhanced <italic>in vivo</italic> neurogenesis in the hippocampus as indicated by increase in neuroblasts, neuronal cells, BrdU<sup>+</sup> cells and PCNA<sup>+</sup> cells. Astrogliosis and gliogenesis were decreased in GFAP/Gp120 Tg mice treated with AM1241, compared with those treated with vehicle.</p> </sec> <sec id="bph12478-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>The CB<sub>2</sub> receptor agonist rescued impaired neurogenesis caused by HIV‐1/Gp120 insult. Thus, CB<sub>2</sub> receptor agonists may act as neuroprotective agents, restoring impaired neurogenesis in patients with HAD.</p> </sec> </abstract>