The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine

     Epilepsy is one of the most prevalent neurological condition characterized by spontaneously non-provoked seizures that occur as a result of a complex disorder of network homeostasis. Current treatments focus on the suppression of these epileptic seizures. However, research has come across evidence for the prevention of epileptogenesis (development and progression of epilepsy) through biochemical manipulations. Detlev Boison, in his review, The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine has discussed this concept via the mechanisms implicated in epileptogenesis and the biochemical interactions between adenosine and glycine which serve as mayor contributors to the development of epilepsy.

     Boisin focuses on temporal lobe epilepsy (TLE), especially its key metabolites adenosine and glycine.  These are primitive biological elements with important biochemical functions, whose homeostasis is generally affected in epileptic brains. Adenosine is an endogenous anticonvulsant and seizure terminator only when the adenosine A1 receptors is activated. Overexpression of its kinase (ADK), results in an adenosine deficiency associated with the increase of astrocytes, known as astrogliosis, and the adenosine receptor (AR) has been linked to the control of DNA methylation under the activity of ADK. The latter is expressed in both cytoplasmic and nuclear isoforms whose functions range from homeostatic regulation to modification in DNA methylation statuses. Astrogliosis is closely related with the increase in ADK expression and the deficiency of adenosine, which leads to the production of seizures and the hypermethylation of DNA. Therefore, it can be concluded that the dysregulation of ADK has a significant effect in the process of turning a normal brain into an epileptic one. Glycine, on the other hand, may have various effects depending on the activation of its presynaptic or postsynaptic receptor (GlyR’s). Low concentrations of glycine have pro-convulsive effects, while high concentrations reduce its occurrence. Its homeostasis is crucial in maintaining a balance in neuronal excitability and its regulation and reuptake is achieved by the glycine transporter 1 (GlyT1). The latter, when increased, is associated with TLE and has been considered a promising target for treatments of cognitive diseases.  

     “The knowledge of epigenetic mechanisms implicated in the development of epilepsy provides a conceptual and mechanistic framework for the future development of epigenetic therapies tailored to prevent epilepsy (antiepileptogenic) or its progression (disease modifying)”(Boison, 2016). The current treatments fail to take into account the causes of epilepsy and are therefore unable to halt epileptogenesis, which is why epigenetic modifications offer new therapeutic alternatives. Using rat models it has been discovered that an adenosine augmentation can effectively reduce and even suppress the occurrence of seizures. They have also been used to form the basis for both the ADK hypothesis (acute insults to the brain such as traumatic brain injury, seizures, or a stroke lead to an acute surge in adenosine associated with transient downregulation of ADK) and the methylation hypothesis of epileptogenesis (suggests that seizures may induce epigenetic modifications aggravating the condition). Alteration in DNA methylation plays a significant role in in the development and progression of neurodegenerative diseases like epilepsy. The increased activity of DNA methylating enzymes and the hypermethylation of DNA has been linked to onset of epilepsy. However, the status of DNA methylation depends on the equilibrium of biochemical enzyme reactions catalyzed by DNA methyltransferases (DNMTs) or Ten-eleven translocations (TET) enzymes. These mechanisms depend on transmethylation pathways controlled by adenosine and glycine concentrations regulated by ADK and GlyT1.

     The biochemical discoveries discussed by Boison have made way for new research areas. Understanding the epigenetics behind epilepsy may be result in the development of novel and effective therapeutic strategies.

 “Challenges for drug development remain. It needs to be determined whether new therapeutic agents can enter the brain and whether a higher level of selectivity for specific isoforms of ADK can be achieved. Due to the different distribution of nucleoside transporters within the brain there might be opportunities for the development of cell-type or isoform selective therapies.” (Boison, 2016).

References:

Boison, D. (2016). The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829603/pdf/fnmol-09-00026.pdf