Cannabis can trigger spontaneous cell death in foetal brain cells, according to new research published by a scientist at Trinity College, Dublin. The work has identified the steps that lead to cell death but also points to potential drug therapies for use in pain relief and cancer treatment.
The study, published this summer in Neuropharmacology, focuses on tetrahydrocannabinol, or THC, the principle psychoactive ingredient of cannabis. "We are proposing that the foetal brain may be more susceptible to damage by THC than the adult brain," says Dr Veronica Campbell, a lecturer in the department of physiology.
She leads a research team looking at THC and the biochemical cascade the drug causes inside the cell. The group includes three postgraduates: Eric Downer, Barry Boland and Marie Fogarty.
They discovered that one of the links in this reaction path triggers apoptosis, or controlled cell death, the body's way of getting rid of old or damaged cells. The research also showed that foetal neurons are particularly susceptible to cell death if exposed to THC.
The drug gets into the bloodstream when any form of cannabis is used. In turn, the THC connects to the "canniboid receptor" on the cell surface, where the drug chemically attaches to tissues. "There is a particular receptor that binds tetrahydrocannabinol and activates a biochemical cascade within the cell," says Campbell.
When this THC connection is made, the cell releases other substances, starting with "G-protein link". This molecule in turn affects the energy factories inside the cell known as the mitochondria. The disturbed mitochondria then release cytochrome C, which triggers the release of caspases. These are enzymes that chop up DNA-repair enzymes, the final step that initiates apoptosis.
The research group was focusing on the second step in the chain, G-protein link, to understand what effect it has on nerve tissues.
The laboratory-based study relies on the use of cultured cell lines, neurons taken from adult and neonate rats. The researchers looked only at neurons and found that THC seldom damaged adult cells.
Neonate cells were highly susceptible to THC, however, with up to 60 per cent of cells damaged or killed off after exposure due to apoptosis.
"The dose we use is consistent with the plasma levels for THC found after exposure to marijuana," says Campbell. "What is interesting from a pharmacological view is, here is a G-protein link involved in the cell-death pathway."
The much greater susceptibility of neonatal tissue suggests that cannabis use during pregnancy may cause significant cell death in the foetus, according to Campbell.
Studies of children born to women who used cannabis regularly during pregnancy showed there was an increased risk of mental deficits. It affected memory skills in particular, she says, but also verbal skills and, in some cases, movement.
These discoveries may lead to valuable new treatments, however. Campbell found that while adult neurons could resist the impact caused by THC, tumour cells were more easily damaged. "Tumour cell lines are susceptible to this toxic effect." This may point to a new type of brain-tumour therapy.
A better understanding of what happens inside a cell after THC exposure is also useful. Research has shown that THC may be valuable in pain relief, and it may be possible to find drugs that connect to the canniboid receptor but don't cause damage.
"The more we know about the chemical pathways of the THC receptor, the better we can develop new agonists of the receptor which lack these neurotoxic effects."
The Trinity group is now looking at why immature neurons are more likely to be damaged than adult cells. It is also analysing which genes are switched on as the cascade occurs and how the released molecules signal to one another.