Δ8-THC Protects against Amyloid Beta Toxicity Modulating ER Stress In Vitro: A Transcriptomic Analysis

Abstract

Alzheimer’s disease (AD) represents the most common form of dementia, characterized by amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs). It is characterized by neuroinflammation, the accumulation of misfolded protein, ER stress and neuronal apoptosis. It is of main importance to find new therapeutic strategies because AD prevalence is increasing worldwide. Cannabinoids are arising as promising neuroprotective phytocompounds. In this study, we evaluated the neuroprotective potential of Δ8-THC pretreatment in an in vitro model of AD through transcriptomic analysis. We found that Δ8-THC pretreatment restored the loss of cell viability in retinoic acid-differentiated neuroblastoma SH-SY5Y cells treated with Aβ1-42. Moreover, the transcriptomic analysis provided evidence that the enriched biological processes of gene ontology were related to ER functions and proteostasis. In particular, Aβ1-42 upregulated genes involved in ER stress and unfolded protein response, leading to apoptosis as demonstrated by the increase in Bax and the decrease in Bcl-2 both at gene and protein expression levels. Moreover, genes involved in protein folding and degradation were also deregulated. On the contrary, Δ8-THC pretreatment reduced ER stress and, as a consequence, neuronal apoptosis. Then, the results demonstrated that Δ8-THC might represent a new neuroprotective agent in AD.

Astaxanthin Inhibits H2O2-Induced Excessive Mitophagy and Apoptosis in SH-SY5Y Cells by Regulation of Akt/mTOR Activation

“…A growing body of studies have indicated that apoptotic cell death plays a critical role in the progression of neurodegenerative diseases [4,5]. The two main apoptotic pathways are the extrinsic pathway, which is initiated by a death ligand binding to a death receptor at the cell membrane, and the intrinsic pathway, which is triggered by the permeabilization of the mitochondrial outer membrane that leads to the release of mitochondrial proteins including cytochrome c and other apoptogenic factors [6].…”

Transcriptomic Profiling after In Vitro Δ8-THC Exposure Shows Cytoskeletal Remodeling in Trauma-Injured NSC-34 Cell Line

“…The choice of the dose was based on previous studies. Indeed, in other previous experiments, we observed no cytotoxicity and the dose of 20 µM Δ 8 -THC was more suitable to reveal its effects [ 17 ].…”

“…In order to obtain 182 mg (yield 91%) of Δ 8 -THC (1) as a brown oil, the residue underwent purification by Gravity Column Chromatography (GCC) on silica gel (pure petroleum ether to petroleum ether-EtOAc 9:1). A further step of purification was performed using JASCO Hichrom, 250 × 25 mm, silica UV−vis detector-2075 plus (silica, petroleum-ether-EtOAc gradient from 95:5 to 85:15), obtaining 150 mg of Δ 8 -THC (99% purity) as a brownish powder, whose structure has been identified in accordance with proton nuclear magnetic resonance ( 1 H NMR) [ 17 ], using Bruker 400 spectrometers (Bruker ® , Billerica, MA, USA), and the results were previously demonstrated [ 23 ]. The residues of solvent were identified as responsible for the chemical shifts (CDCl 3 : δH = 7.26).…”

“…Actually, Δ 8 -THC seems to better influence the activity of glutamatergic and cholinergic synapses [ 16 ]. Additionally, this molecule was also able to provide a neuroprotective effect against amyloid beta (Aβ 1–42 ), reducing the stress on the endoplasmic reticulum with a consequent drop of neuronal apoptosis [ 17 ]. Thus, Δ 8 -THC could effectively protect neuronal cells from death by modulating different cell survival and promoting neuroprotection.…”

Possible Role of Cannabis in the Management of Neuroinflammation in Patients with Post-COVID Condition

“…THC has not been shown to reduce proinflammatory cytokine levels or to increase anti-inflammatory cytokines in models of neurological diseases, although significant improvements in neuropathic pain have been reported [75,103,104]. However, THC has recently been proposed as a new neuroprotective agent in Alzheimer's disease due to its ability to restore cell viability in retinoic acid-differentiated neuroblastoma SH-SY5Y cells and upregulate genes involved in endoplasmic reticulum stress and the unfolded protein response [105]. Additionally, it was demonstrated that THC (5 mg) combined with codeine (50 mg) exhibited analgesic and antispastic effects in a patient with spasticity and pain due to spinal cord injury [106].…”