A role for p53 in the regulation of lysosomal permeability by delta 9-tetrahydrocannabinol in rat cortical neurones: implications for neurodegeneration.
Aoife Gowran, Veronica A Campbell
Journal of Neurochemistry May 2008 DOI: 10.1111/j.1471-4159.2008.05278.x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro cell study Peer reviewed |
|---|---|
| Population | Cultured cortical neurones |
| Interventions | Delta9-tetrahydrocannabinol (Delta9-THC) AM251 pifithrin-alpha cathepsin-D inhibitor |
| Dose | 10 microM cathepsin-D inhibitor |
| Topics | Cannabis |
| Key points | Delta9-THC promotes lysosomal permeability in cultured cortical neurones via a CB1 receptor- and p53-dependent mechanism, releasing cathepsin-D into the cytosol; blocking cathepsin-D with a 10 microM cell-permeable inhibitor prevented Delta9-THC-induced apoptosis, indicating lysosomal instability is an early event in this apoptotic cascade. |
Abstract
The psychoactive ingredient of marijuana, Delta9-tetrahydrocannabinol (Delta9-THC), can evoke apoptosis in cultured cortical neurones. Whilst the intracellular mechanisms responsible for this apoptotic pathway remain to be fully elucidated, we have recently identified a role for the CB1 type of cannabinoid (CB) receptor and the tumour suppressor protein, p53. In the current study, we demonstrate the Delta9-THC promotes a significant increase in lysosomal permeability in a dose- and time-dependent manner. The increase in lysosomal permeability was blocked by the CB1 receptor antagonist, AM251. Delta9-THC increased the localization of phospho-p53Ser15 at the lysosome and stimulated the release of the lysosomal cathepsin enzyme, cathepsin-D, into the cytosol. The p53 inhibitor, pifithrin-alpha and small interfering RNA-mediated knockdown of p53 prevented the Delta9-THC-mediated increase in lysosomal permeability. Furthermore, the Delta9-THC -mediated induction of apoptosis was abrogated by a cell-permeable cathepsin-D inhibitor (10 microM). Thus, the study demonstrates that Delta9-THC impacts on the lysosomal system, via p53, to evoke lysosomal instability as an early event in the apoptotic cascade. This provides evidence for a novel link between the CB1 receptor and the lysosomal branch of the apoptotic pathway which is crucial in regulating neuronal viability following exposure to Delta9-THC.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
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