Cannabinoid Receptor CB1 Is Involved in Nicotine-Induced Protection Against Aβ1–42 Neurotoxicity in HT22 Cells
Abstract Emerging evidences suggest that nicotine exerts a neuroprotective effect on Alzheimer’s disease (AD), yet the precise mechanism is not fully elucidated. Here, HT22 cells were exposed to amyloid beta protein fragment (Aβ)1–42 to mimic the pathological process of neuron in AD. We hypothesized that cannabinoid receptor CB1 is involved in the nicotine-induced neuroprotection against Aβ1–42 injury in HT22 cells. CB1 expression in HT22 cells was investigated by immunocytochemistry and Western blot. The injury of HT22 cells was evaluated by cellular morphology, cell viability, and lactate dehydrogenase (LDH) release. The apoptosis of HT22 cells was assessed by flow cytometry and expressionsofBcl-2andBax.Theresultsdemonstratedthatnicotine markedly upregulated CB1 expression, increased cell viability, ameliorated cellular morphology, decreased LDH release, andreduced the apoptotic rateofHT22 cells exposed to Aβ1– 42 for 24 h, while the blockade of CB1 or the inhibition of proteinkinaseC(PKC)partiallyreversedtheneuroprotection. Furthermore, the blockade of CB1 reversed nicotine-induced PKC activation in HT22 cells exposed to Aβ1–42. These results suggest that CB1 is involved in the nicotine-induced neuroprotection against Aβ1–42 neurotoxicity, and the neuroprotection may be dependent on the activation of PKC.
Cannabinoid CB2 Receptor Mediates Nicotine-Induced Anti-Inflammation in N9 Microglial Cells Exposed to
Macamides are a distinct class of secondary metabolites, benzylamides of long chain fatty acids, which were isolated from the Peruvian plant Lepidium meyenii (Maca). As structural analogues of the endocannabinoid anandamide (AEA),they havedemonstrated neuroprotective effectsin vitro andin vivo. Thepurposeofthis study was to demonstrate the neuroprotective activity of the macamides: N-(3-methoxybenzyl)oleamide (MAC 18:1), N-(3-methoxybenzyl)linoleamide (MAC 18:2) and N-(3-methoxybenzyl)linolenamide (MAC 18:3) in a neurotoxic environment caused by exposure of U-87 MG glioblastoma cells to manganese chloride (MnCl2). The neuroprotective effects of these macamides were reversed by the CB1 antagonist AM251. The mechanism by which manganese (Mn) induces cell damage was investigated by studying its effects on mitochondria. Reactive oxygen species (ROS) increase intracellular calcium and enhance the opening of mitochondrial permeability transition pores (MPTP), which leads to decreased mitochondrial membrane potential (MMP), to disruption of mitochondria andtoneurondeathinneurodegenerative disorders. Inthisstudy, MnCl2 at50μMwasresponsible for mitochondrial disruption, which was attenuated by all three of the macamides tested. Human peroxisome proliferator-activated receptor gamma (PPARγ) has been proposed to be a cannabinoid target, and PPARγ has also been demonstrated to mediate some of the longer-term vascular effects of the plant cannabinoid, Δ9-tetrahydrocannabinol. PPARγactivation wasobservedinresponsetoexposuresofcellstoMAC18:2andMAC18:3. These findings suggest that macamides achieve their neuroprotective effects by binding to CB1 receptors to protect against Mn-induced toxicity in U-87 MG glioblastoma cells. Additionally these macamides, in a manner similartotheanalogous endocannabinoidAEA,interactwithothertargetssuchasPPARγtoregulatemetabolism and energy homeostasis, cell differentiation and inflammation.
Edited by Ruth, 21 September 2018 - 06:19 AM.
