Abstract
Cannabis is the most commonly used illegal drug of abuse in Western society. Δ9-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, CB1. In this study we report that tetrahydrocannabinol (5 μM) evokes a rapid phosphorylation, and thus activation, of the tumour suppressor protein, p53, in a manner involving the cannabinoid CB1 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-α (100 nM). The tetrahydrocannabinol-induced activation of the pro-apoptotic cysteine protease, caspase-3, and DNA fragmentation was also blocked by pifithrin-α. 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.
| Original language | English |
|---|---|
| Pages (from-to) | 57-65 |
| Number of pages | 9 |
| Journal | European Journal of Pharmacology |
| Volume | 564 |
| Issue number | 1-3 |
| DOIs | |
| Publication status | Published - Jun 14 2007 |
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Keywords
- Apoptosis
- p53
- Tetrahydrocannabinol
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Pharmacology
Cite this
The tumour suppressor protein, p53, is involved in the activation of the apoptotic cascade by Δ9-tetrahydrocannabinol in cultured cortical neurons. / Downer, Eric J.; Gowran, Aoife; Murphy, Áine C.; Campbell, Veronica A.
In: European Journal of Pharmacology, Vol. 564, No. 1-3, 14.06.2007, p. 57-65.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The tumour suppressor protein, p53, is involved in the activation of the apoptotic cascade by Δ9-tetrahydrocannabinol in cultured cortical neurons
AU - Downer, Eric J.
AU - Gowran, Aoife
AU - Murphy, Áine C.
AU - Campbell, Veronica A.
PY - 2007/6/14
Y1 - 2007/6/14
N2 - Cannabis is the most commonly used illegal drug of abuse in Western society. Δ9-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, CB1. In this study we report that tetrahydrocannabinol (5 μM) evokes a rapid phosphorylation, and thus activation, of the tumour suppressor protein, p53, in a manner involving the cannabinoid CB1 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-α (100 nM). The tetrahydrocannabinol-induced activation of the pro-apoptotic cysteine protease, caspase-3, and DNA fragmentation was also blocked by pifithrin-α. 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.
AB - Cannabis is the most commonly used illegal drug of abuse in Western society. Δ9-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, CB1. In this study we report that tetrahydrocannabinol (5 μM) evokes a rapid phosphorylation, and thus activation, of the tumour suppressor protein, p53, in a manner involving the cannabinoid CB1 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-α (100 nM). The tetrahydrocannabinol-induced activation of the pro-apoptotic cysteine protease, caspase-3, and DNA fragmentation was also blocked by pifithrin-α. 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.
KW - Apoptosis
KW - p53
KW - Tetrahydrocannabinol
UR - http://www.scopus.com/inward/record.url?scp=34250687550&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34250687550&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2007.02.025
DO - 10.1016/j.ejphar.2007.02.025
M3 - Article
VL - 564
SP - 57
EP - 65
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1-3
ER -