In his CURE-funded research, Dr. Detlev Boison and his team found that an adenosine kinase inhibitor called 5-ITU increases adenosine levels in the brain, protecting it from seizures.
- CURE Grantee Dr. Detlev Boison and his team discovered that short-term use of a substance called 5-ITU prevents epilepsy from developing in mouse models of acquired epilepsy.
- 5-ITU inhibits a brain enzyme called adenosine kinase (ADK) that regulates a substance called adenosine (ADO), which, in turn, plays a critical role in preventing epilepsy following an injury to the brain.
- Dr. Boison’s groundbreaking work supports the development of improved, more selective treatments which aim to cure underlying causes of epilepsy, rather than merely control seizures.
One of the most common ways of developing epilepsy is through “acquired” means, such as a severe concussion, brain infection, fever-induced seizure, or stroke. A naturally occurring substance in the brain, called adenosine (ADO), plays a protective role by decreasing excessive neuronal activity1,2 and protecting the DNA in nerve cells from changes that contribute to the development of epilepsy.3 ADO levels in the brain are regulated by an enzyme called adenosine kinase (ADK) and, unfortunately, brain injuries often trigger a series of events that elevate levels of ADK. In his CURE-funded research, Dr. Detlev Boison and his team found that an ADK inhibitor called 5-ITU increases ADO levels in the brain and protects it from seizures.
To make this discovery, the team evaluated if short-term treatment of 5-ITU following an injury to the brain could halt the development of epilepsy over the long-term.4 To do so, they used a mouse model of acquired epilepsy that reliably develops seizures two weeks after an injury. The team first had to determine the appropriate time points to administer 5-ITU following a head injury. Over a two-week period, the team monitored the progression of brain tissue damage in their mouse model, along with ADK levels and changes in EEG, analyzing samples at different days post-injury compared to controls. The team found that by the third day, ADK levels had started to increase and continued to increase over the two-week time period, accompanied by a loss of neurons in an area of the brain called the hippocampus and changes in EEG patterns by the fourteenth day post-injury.
Reasoning that 5-ITU should first be administered when ADK levels initially rise, the team gave their mouse model the substance for a limited time – for only five days starting on day 3 post-injury – and continued to monitor the mice closely. After six weeks, the team found that the 5-ITU-treated mice had little brain tissue damage, significantly decreased ADK levels, and fewer seizures compared to the control group. Importantly, these changes were sustained even after nine weeks.
Discovering that short-term inhibition of ADK leads to a long-lasting antiepileptogenic effect makes this a promising therapy, especially since it could avoid any potential toxicities and intolerable side effects from long-term use of ADK inhibitors. Such a treatment would represent a true cure for epilepsy. Dr. Boison’s groundbreaking research supports the development of improved, more selective compounds which can one day be tested in clinical trials and, hopefully, approved for clinical use.
1 Fedele, D.E. et al. Engineering embryonic stem cell derived glia for adenosine delivery. Neurosci. Lett. 2004; 370(2-3) 160-165.
2 Guttinger, M. et al. Suppression of kindled seizures by paracrine adenosine release from stem cell-derived brain implants. Epilepsia 2005 46(8): 1162-1169.
3 Williams-Karnesky, R.L. et al. Epigenetic changes induced by adenosine augmentation therapy prevent epilpetogenesis. J. Clin. Invest. 2013; 123(8): 3552-3563
4 Sandau, U.S. et al. Transient use of a systemic adenosine kinase inhibitor attenuates epilepsy development in mice. Epilepsia 2019; 60: 615-625.
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