Impaired neurogenesis by HIV-1-Gp120 is rescued by genetic deletion of fatty acid amide hydrolase enzyme.

Abstract

BACKGROUND AND PURPOSE:

The HIV-envelope glycoprotein Gp120 is involved in neuronal injury and is associated with neuro-AIDS pathogenesis in the brain. Endocannabinoids are important lipid ligands in the CNS regulating neural functions, and their degeneration is controlled by hydrolysing enzymes such as the fatty acid amide hydrolase (FAAH). Here, we examined whether in vivo genetic deletion of Faah gene prevents HIV-1 Gp120-mediated effects on neurogenesis.

EXPERIMENTAL APPROACH:

We generated new GFAP/Gp120 transgenic (Tg) mice that have genetic deletion of Faah gene by mating glial fribillary acidic protein (GFAP)/Gp120 Tg mice with Faah-/- mice. Neurogenesis and cell death were assessed by immunocytochemical analysis.

KEY RESULTS:

Endocannabinoid levels in the brain of the double GFAP/Gp120//Faah-/- mice were similar to those observed in Faah-/- mice. However, unlike the impaired neurogenesis observed in GFAP/Gp120 Tg mice and Faah-/- mice, these GFAP/Gp120//Faah-/ mice showed significantly improved neurogenesis in the hippocampus, indicated by a significant increase in neuroblasts and neuronal cells, an increase in BrdU(+) cells and doublecortin positive cells (DCX(+) ), and an increase in the number of PCNA. Furthermore, a significant decrease in astrogliosis and gliogenesis was observed in GFAP/Gp120//Faah-/-mice and neurogenesis was stimulated by neural progenitor cells (NPCs) and/or the newly formed NPC niches characterized by increased COX-2 expression and elevated levels of PGE2 .

CONCLUSIONS AND IMPLICATIONS:

In vivo genetic ablation of Faah, resulted in enhanced neurogenesis through modulation of the newly generated NPC niches in GFAP/Gp120//Faah-/- mice. This suggests a novel approach of using FAAH inhibitors to enhance neurogenesis in HIV-1 infected brain.

• Authors: H K Avraham, S Jiang, Y Fu, E Rockenstein, A Makriyannis, J Wood, L Wang, E Masliah, S Avraham
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 172 Issue 19 Pg. 4603-14 (Oct 2015) ISSN: 1476-5381 [Electronic] England
• PMID: 24571443 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

Chemical References

• Dcx protein, mouse
• Doublecortin Protein
• Endocannabinoids
• Glial Fibrillary Acidic Protein
• HIV Envelope Protein gp120
• glial fibrillary astrocytic protein, mouse
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Amidohydrolases
• fatty-acid amide hydrolase
• Dinoprostone

Topics

• Amidohydrolases (genetics)
• Animals
• Brain (metabolism)
• Cyclooxygenase 2 (metabolism)
• Dinoprostone (metabolism)
• Doublecortin Protein
• Endocannabinoids (metabolism)
• Gene Deletion
• Glial Fibrillary Acidic Protein (genetics)
• HIV Envelope Protein gp120 (genetics)
• Mice, Transgenic
• Neurogenesis (genetics, physiology)