Funding for the MECPST-IPD project to Dr Martin Egeland, at Kings College London, UK, supported research into the impact of the drug temozolomide on neurogenesis and the relationship between depleted neurogenesis and depression. A paper he co-authored, presenting the team’sfindings, has now been published in the ‘Journal of Translational Psychiatry’.
The link between depression, adult neurogenesis and antidepressants has been an area of intense interest for researchers over the past decade. But a barrier to establishing whether what is indicated in vitro and in animal studies applies also to the human brain has been, naturally, the fact that it is unethical to decrease adult neurogenesis for the sake of experimentation.
However as TMZ is an antimitotic drug, (one which inhibits mitosis, commonly known as cell division), it is likely to decrease adult neurogenesis as a side effect. As such, studying its impact offers fresh insight into what impact such a decrease has on the brain, along with the links between the decrease and depression.
Some research shows prevalence rates of depression, apparently highly under diagnosed, may be hitting as many as 90% of patients. While they used mice in their animal studies, they report the level of hippocampal adult neurogenesis in humans may be even greater than in rodents, making the question, ‘Is there a link?’ even more pressing.
What happens to behaviour and mood when neurogenesis is decreased?
An experimental and a control group of mice were established. The TMZ and saline solution vehicle were injected into the former while the latter received injections of the saline solution alone. To mimic the cyclic treatment administered in the clinic, the animals were injected on 3 consecutive days every week for a total of 6 weeks and were were then allowed to recover for a period of 6 weeks.
They were tested for their reaction to novelty – their latency in accessing a food pellet placed in the middle of a new environment for which food consumption over 24 hours was measured to control for changes in appetite. Tests also assessed their sucrose preference and analysed their reactions to illuminated and shaded areas, along with other parameters relevant to depression such as stress levels. Blood tests were conducted and, the experiments having run their course, the mice were then carefully euthanized. Brain samples were collected and analysed nine weeks following the end of the TMZ treatment.
Having devised a new method of coronal sectioning to boost accuracy, the team found that TMZ caused sustained decreases in neurogenesis, particularly in the ventral dentate gyrus. Blood tests revealed that stress induced a greater increase in corticosterone in mice treated with the drug. However, results showed no real difference in anxiety levels between treated and control groups.
They sum up their findings by stating, ‘(…) this study gives strong evidence that chemotherapy-induced decreases in adult neurogenesis may affect the stress response and behaviours related to processing novelty, both of which ultimately may contribute to depressive symptoms.’
From theory to practice
The work conducted by Dr Egeland, under the MECPST-IPD (Identification of inflammation pathways involved in the predisposition to decreased neurogenesis and depression) project, and his colleagues has particular relevance to cancer patients being treated with TMZ. However as all forms of chemotherapy act on cell division, their findings are relevant to many drugs used in chemotherapy.
Being aware that such treatments could expose a patient to the risk of depression would enable clinicians to alert them to the possibility. In the long term, the team would be interested to know if certain interventions in cancer patients, such as cognitive training, can increase their neurogenic reserve before they go on to chemotherapy, thereby protecting them from the side effects of their treatment. Treating the cancer is the priority of course but if the patient’s quality of life can be improved it may reduce their vulnerability to mental health problems.
Source : CORDIS