The Cannabinoid CB₂ Receptor Agonist AM1241 Enhances Neurogenesis in GFAP/Gp120 Transgenic Mice Displaying Deficits in Neurogenesis

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2013 Oct 24

PMID 24148086

Citations 54

Authors

Hava Karsenty Avraham

Shuxian Jiang

Yigong Fu

Edward Rockenstein

Alexandros Makriyannis

Alexander Zvonok

Eliezer Masliah

Shalom Avraham

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: 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.

Experimental Approach: 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.

Key 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 And Implications: 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.

Citing Articles

Therapeutic potential of EVs loaded with CB2 receptor agonist in spinal cord injury via the Nrf2/HO-1 pathway.

Shaikh I, Bhandari R, Singh S, Zhu X, Shahzad K, Shao C Redox Rep. 2024; 29(1):2420572.

PMID: 39466990 PMC: 11520104. DOI: 10.1080/13510002.2024.2420572.

The Impact of Cannabis Use on Cognition in People with HIV: Evidence of Function-Dependent Effects and Mechanisms from Clinical and Preclinical Studies.

Ayoub S, Holloway B, Miranda A, Roberts B, Young J, Minassian A Curr HIV/AIDS Rep. 2024; 21(3):87-115.

PMID: 38602558 PMC: 11129923. DOI: 10.1007/s11904-024-00698-w.

URB447 Is Neuroprotective in Both Male and Female Rats after Neonatal Hypoxia-Ischemia and Enhances Neurogenesis in Females.

Beldarrain G, Chillida M, Hilario E, Herrero de la Parte B, Alvarez A, Alonso-Alconada D Int J Mol Sci. 2024; 25(3).

PMID: 38338884 PMC: 10855747. DOI: 10.3390/ijms25031607.

Effects of acute Δ-tetrahydrocannabinol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice.

Yadav-Samudrala B, Gorman B, Dodson H, Ramineni S, Wallace E, Peace M Brain Res. 2023; 1822:148638.

PMID: 37858856 PMC: 10873064. DOI: 10.1016/j.brainres.2023.148638.

Role of integrating cannabinoids and the endocannabinoid system in neonatal hypoxic-ischaemic encephalopathy.

Xiao J, Zhou Y, Sun L, Wang H Front Mol Neurosci. 2023; 16:1152167.

PMID: 37122621 PMC: 10130673. DOI: 10.3389/fnmol.2023.1152167.

References

Mucke L, Abraham C, Ruppe M, Rockenstein E, Toggas S, Mallory M . Protection against HIV-1 gp120-induced brain damage by neuronal expression of human amyloid precursor protein. J Exp Med. 1995; 181(4):1551-6. PMC: 2191956. DOI: 10.1084/jem.181.4.1551. View

Kilkenny C, Browne W, Cuthill I, Emerson M, Altman D . Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol. 2010; 160(7):1577-9. PMC: 2936830. DOI: 10.1111/j.1476-5381.2010.00872.x. View

Tran P, Ren D, Miller R . The HIV-1 coat protein gp120 regulates CXCR4-mediated signaling in neural progenitor cells. J Neuroimmunol. 2005; 160(1-2):68-76. PMC: 2746240. DOI: 10.1016/j.jneuroim.2004.11.001. View

van der Stelt M, Veldhuis W, Bar P, Veldink G, Vliegenthart J, Nicolay K . Neuroprotection by Delta9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. J Neurosci. 2001; 21(17):6475-9. PMC: 6763099. View

Krucker T, Toggas S, Mucke L, Siggins G . Transgenic mice with cerebral expression of human immunodeficiency virus type-1 coat protein gp120 show divergent changes in short- and long-term potentiation in CA1 hippocampus. Neuroscience. 1998; 83(3):691-700. DOI: 10.1016/s0306-4522(97)00413-2. View

Mattson M, Haughey N, Nath A . Cell death in HIV dementia. Cell Death Differ. 2005; 12 Suppl 1:893-904. DOI: 10.1038/sj.cdd.4401577. View

Toggas S, Masliah E, Mucke L . Prevention of HIV-1 gp120-induced neuronal damage in the central nervous system of transgenic mice by the NMDA receptor antagonist memantine. Brain Res. 1996; 706(2):303-7. DOI: 10.1016/0006-8993(95)01197-8. View

Sarne Y, Mechoulam R . Cannabinoids: between neuroprotection and neurotoxicity. Curr Drug Targets CNS Neurol Disord. 2005; 4(6):677-84. DOI: 10.2174/156800705774933005. View

Kim H, Shin A, Thayer S . Activation of cannabinoid type 2 receptors inhibits HIV-1 envelope glycoprotein gp120-induced synapse loss. Mol Pharmacol. 2011; 80(3):357-66. PMC: 3164336. DOI: 10.1124/mol.111.071647. View

10.

Ibrahim M, Deng H, Zvonok A, Cockayne D, Kwan J, Mata H . Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A. 2003; 100(18):10529-33. PMC: 193595. DOI: 10.1073/pnas.1834309100. View

11.

Ibrahim M, Porreca F, Lai J, Albrecht P, Rice F, Khodorova A . CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A. 2005; 102(8):3093-8. PMC: 549497. DOI: 10.1073/pnas.0409888102. View

12.

Katona I, Freund T . Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med. 2008; 14(9):923-30. DOI: 10.1038/nm.f.1869. View

13.

Marchalant Y, Brothers H, Norman G, Karelina K, DeVries A, Wenk G . Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis. Neurobiol Dis. 2009; 34(2):300-7. DOI: 10.1016/j.nbd.2009.01.014. View

14.

Shah A, Kumar A . HIV-1 gp120-mediated increases in IL-8 production in astrocytes are mediated through the NF-κB pathway and can be silenced by gp120-specific siRNA. J Neuroinflammation. 2010; 7:96. PMC: 3023744. DOI: 10.1186/1742-2094-7-96. View

15.

Palazuelos J, Ortega Z, Diaz-Alonso J, Guzman M, Galve-Roperh I . CB2 cannabinoid receptors promote neural progenitor cell proliferation via mTORC1 signaling. J Biol Chem. 2011; 287(2):1198-209. PMC: 3256884. DOI: 10.1074/jbc.M111.291294. View

16.

Wiley C, Achim C, Christopherson C, Kidane Y, Kwok S, Masliah E . HIV mediates a productive infection of the brain. AIDS. 1999; 13(15):2055-9. DOI: 10.1097/00002030-199910220-00007. View

17.

Galve-Roperh I, Aguado T, Palazuelos J, Guzman M . Mechanisms of control of neuron survival by the endocannabinoid system. Curr Pharm Des. 2008; 14(23):2279-88. DOI: 10.2174/138161208785740117. View

18.

Walsh K, Megyesi J, Wilson J, Crukley J, Laubach V, Hammond R . Antioxidant protection from HIV-1 gp120-induced neuroglial toxicity. J Neuroinflammation. 2004; 1(1):8. PMC: 483061. DOI: 10.1186/1742-2094-1-8. View

19.

Aguado T, Monory K, Palazuelos J, Stella N, Cravatt B, Lutz B . The endocannabinoid system drives neural progenitor proliferation. FASEB J. 2005; 19(12):1704-6. DOI: 10.1096/fj.05-3995fje. View

20.

Iskander S, Walsh K, Hammond R . Human CNS cultures exposed to HIV-1 gp120 reproduce dendritic injuries of HIV-1-associated dementia. J Neuroinflammation. 2004; 1(1):7. PMC: 483060. DOI: 10.1186/1742-2094-1-7. View