ThePineapple - Journal Club #50: RhoA/ROCK | Astrocytes | Adrenoleukodystrophy | Pregnancy

Journal Club #50: RhoA/ROCK, Astrocytes, Adrenoleukodystrophy, Pregnancy

Week of 07-17-22

The field of cannabis science is both small and also unimaginably big at the same time. In relative terms there is still a lot that we don’t know about how the endocannabinoid system interacts with the rest of the body. If you compare the number of weekly cannabinoid publications with a field like immunology  then the number of papers being published every week is fairly small. But yet, because the endocannabinoid system is so ubiquitous throughout the body it is also unimaginably big, as discoveries about the endocannabinoid system feed directly into immunology, neurology and many others. Scientific discoveries about the endocannabinoid system increasingly appear to be quite relevant beyond the immediate scope. For example, this week we selected a paper that shows how genetic inactivation of the CB1 receptor disrupts oligodendrogenesis and the process of myelination via a RhoA/ROCK dependent pathway. But as every week we have 3 more papers that are interesting. First, a study on endocannabinoid signaling in astrocytes. Second a study on the role of CB2 receptor in adrenoleukodystrophy and last but not least a preclinical paper on the effects of prenatal exposure to THC and/or nicotine. 

Note: This is a post for cannabis scientists. A weekly curation of fresh papers that help advance our understanding of cannabis and the endocannabinoid system. 

Cannabinoid CB1 receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice.

Sánchez-de la Torre A, Aguado T, Huerga-Gómez A, Santamaría S, Gentile A, Chara JC, Matute C, Monory K, Mato S, Guzmán M, Lutz B, Galve-Roperh I, Palazuelos J. 

Cell Death Dis. 2022 Jul 7;13(7):585.

Cannabinoids are known to modulate oligodendrogenesis and developmental CNS myelination. However, the cell-autonomous action of these compounds on oligodendroglial cells in vivo, and the molecular mechanisms underlying these effects have not yet been studied. Here, by using oligodendroglial precursor cell (OPC)-targeted genetic mouse models, we show that cannabinoid CB1 receptors exert an essential role in modulating OPC differentiation at the critical periods of postnatal myelination. We found that selective genetic inactivation of CB1 receptors in OPCs in vivo perturbs oligodendrogenesis and postnatal myelination by altering the RhoA/ROCK signaling pathway, leading to hypomyelination, and motor and cognitive alterations in young adult mice. Conversely, pharmacological CB1 receptor activation, by inducing E3 ubiquitin ligase-dependent RhoA proteasomal degradation, promotes oligodendrocyte development and CNS myelination in OPCs, an effect that was not evident in OPC-specific CB1 receptor-deficient mice. Moreover, pharmacological inactivation of ROCK in vivo overcomes the defects in oligodendrogenesis and CNS myelination, and behavioral alterations found in OPC-specific CB1 receptor-deficient mice. Overall, this study supports a cell-autonomous role for CB1 receptors in modulating oligodendrogenesis in vivo, which may have a profound impact on the scientific knowledge and therapeutic manipulation of CNS myelination by cannabinoids.

doi: 10.1038/s41419-022-05032-z. PMID: 35798697; PMCID: PMC9263142.

Endocannabinoid signaling in astrocytes.

Eraso-Pichot A, Pouvreau S, Olivera-Pinto A, Gomez-Sotres P, Skupio U, Marsicano G. 

Glia. 2022 Jul 13. 

The study of the astrocytic contribution to brain functions has been growing in popularity in the neuroscience field. In the last years, and especially since the demonstration of the involvement of astrocytes in synaptic functions, the astrocyte field has revealed multiple functions of these cells that seemed inconceivable not long ago. In parallel, cannabinoid investigation has also identified different ways by which cannabinoids are able to interact with these cells, modify their functions, alter their communication with neurons and impact behavior. In this review, we will describe the expression of different endocannabinoid system members in astrocytes. Moreover, we will relate the latest findings regarding cannabinoid modulation of some of the most relevant astroglial functions, namely calcium (Ca2+ ) dynamics, gliotransmission, metabolism, and inflammation.

doi: 10.1002/glia.24246. Epub ahead of print. PMID: 35822691.

Activating cannabinoid receptor 2 preserves axonal health through GSK-3β/NRF2 axis in adrenoleukodystrophy.

Parameswaran J, Goicoechea L, Planas-Serra L, Pastor A, Ruiz M, Calingasan NY, Guilera C, Aso E, Boada J, Pamplona R, Portero-Otín M, de la Torre R, Ferrer I, Casasnovas C, Pujol A, Fourcade S.

Acta Neuropathol. 2022 Aug;144(2):241-258. 

Aberrant endocannabinoid signaling accompanies several neurodegenerative disorders, including multiple sclerosis. Here, we report altered endocannabinoid signaling in X-linked adrenoleukodystrophy (X-ALD), a rare neurometabolic demyelinating syndrome caused by malfunction of the peroxisomal ABCD1 transporter, resulting in the accumulation of very long-chain fatty acids (VLCFAs). We found abnormal levels of cannabinoid receptor 2 (CB2r) and related endocannabinoid enzymes in the brain and peripheral blood mononuclear cells (PBMCs) of X-ALD patients and in the spinal cord of a murine model of X-ALD. Preclinical treatment with a selective agonist of CB2r (JWH133) halted axonal degeneration and associated locomotor deficits, along with normalization of microgliosis. Moreover, the drug improved the main metabolic disturbances underlying this model, particularly in redox and lipid homeostatic pathways, including increased lipid droplets in motor neurons, through the modulation of the GSK-3β/NRF2 axis. JWH133 inhibited Reactive Oxygen Species elicited by excess VLCFAs in primary microglial cultures of Abcd1-null mice. Furthermore, we uncovered intertwined redox and CB2r signaling in the murine spinal cords and in patient PBMC samples obtained from a phase II clinical trial with antioxidants (NCT01495260). These findings highlight CB2r signaling as a potential therapeutic target for X-ALD and perhaps other neurodegenerative disorders that present with dysregulated redox and lipid homeostasis.

doi: 10.1007/s00401-022-02451-2. Epub 2022 Jul 1. PMID: 35778568.

Effects of Prenatal Nicotine, THC, or Co-Exposure on Cognitive Behaviors in Adolescent Male and Female Rats.

Lallai V, Manca L, Sherafat Y, Fowler CD. 

Nicotine Tob Res. 2022 Jul 13;24(8):1150-1160. 

Although there has been a decrease in the prevalence of tobacco smoking, exposure to nicotine during pregnancy remains a substantial problem worldwide. Further, given the recent escalation in e-cigarette use and legalization of cannabis, it has become essential to understand the effects of nicotine and cannabinoid co-exposure during early developmental stages. We systematically examined the effects of nicotine and/or THC prenatal exposure on cognitive behaviors in male and female offspring. Dams were exposed to nicotine vape or vehicle, and oral edible THC or vehicle, throughout pregnancy. Adolescent offspring were then tested in the prepulse inhibition test, novel object recognition task, and novelty suppressed feeding task. At birth, pups from mothers exposed to nicotine vape or oral THC exhibited reduced body weight, compared to control pups. Prenatal nicotine vape exposure resulted in a decreased baseline startle reactivity in adolescent male and female rats, and in females, enhanced sensorimotor gating in the prepulse inhibition test. Prenatal nicotine and THC co-exposure resulted in significant deficits in the prepulse inhibition test in males. Deficits in short-term memory were also found in males prenatally exposed to THC, either alone or with nicotine co-exposure, and in females exposed to THC alone. Finally, in males, a modest increase in anxiety-associated behaviors was found with THC or nicotine exposure in the latency to approach a novel palatable food. These studies demonstrate differential effects of prenatal exposure to e-cigarette nicotine vape and/or edible THC on cognitive function, with differing effects within male and female groups.
Implications: These studies demonstrate an impact of nicotine, THC, or co-exposure during early developmental stages in utero on behavioral outcomes in adolescence. These findings have important translational implications given the continued use of nicotine and THC containing products by pregnant women worldwide, which can be applied to support healthcare and policy efforts restricting nicotine and THC use during pregnancy.

doi: 10.1093/ntr/ntac018. PMID: 35090174.