The tumour suppressor protein, p53, is involved in the activation of the apoptotic cascade by Delta9-tetrahydrocannabinol in cultured cortical neurons.
Eric J Downer, Aoife Gowran, Aine C Murphy, Veronica A Campbell
European Journal of Pharmacology June 14, 2007 DOI: 10.1016/j.ejphar.2007.02.025 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro laboratory study Peer reviewed |
|---|---|
| Population | Cultured cortical neurons |
| Interventions | Tetrahydrocannabinol Pifithrin-alpha siRNA knockdown of p53 |
| Dose | 5 muM tetrahydrocannabinol; 100 nM pifithrin-alpha |
| Topics | Cannabis |
| Key points | Tetrahydrocannabinol (5 micromolar) activates p53 via the CB1 receptor and JNK in cultured cortical neurons, increasing Bax expression and Bcl phosphorylation. Blocking p53 with pifithrin-alpha (100 nM) or siRNA knockdown prevented THC-induced caspase-3 activation and DNA fragmentation, indicating p53 is required for THC-induced neuronal apoptosis. |
Abstract
Cannabis is the most commonly used illegal drug of abuse in Western society. Delta(9)-tetrahydrocannabinol, the psychoactive ingredient of marijuana, regulates a variety of neuronal processes including neurotransmitter release and synaptic transmission. An increasing body of evidence suggests that cannabinoids play a key role in the regulation of neuronal viability. In cortical neurons tetrahydrocannabinol has a neurodegenerative effect, the mechanisms of which are poorly understood, but involve the cannabinoid receptor subtype, CB(1). In this study we report that tetrahydrocannabinol (5 muM) evokes a rapid phosphorylation, and thus activation, of the tumour suppressor protein, p53, in a manner involving the cannabinoid CB(1) receptor, and the stress-activated protein kinase, c-jun N-terminal kinase, in cultured cortical neurons. Tetrahydrocannabinol increased expression of the p53-transcriptional target, Bax and promoted Bcl phosphorylation. These events were abolished by the p53 inhibitor, pifithrin-alpha (100 nM). The tetrahydrocannabinol-induced activation of the pro-apoptotic cysteine protease, caspase-3, and DNA fragmentation was also blocked by pifithrin-alpha. A siRNA knockdown of p53 further verified the role of p53 in tetrahydrocannabinol-induced apoptosis. This study demonstrates a novel cannabinoid signalling pathway involving p53 that culminates in neuronal apoptosis.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.