An NAD+ consuming enzyme is a new target to protect against epilepsy-induced brain damage(Gilnature | iStock)
· The levels of CD38, an NAD+ consuming enzyme, increase in brain cells during epilepsy.
· CD38 emerges as an interesting new target in epilepsy.
With spontaneous recurrent seizure activity — a condition called epilepsy — people can develop brain damage due to the over-stimulation of brain cells. Essentially, your brain cells get fried. We know some of the brain regions vulnerable to epilepsy-induced brain damage, a process called epileptogenesis, but we still have a poor grasp on what exactly is going on in the affected brain cells.
In an article published in Brain Research, Khodaverdiana and colleagues show that during seizures and epileptogenesis in mice there is a dramatic decline in the levels of nicotinamide adenine dinucleotide (NAD+). Corresponding with this decrease in NAD+ levels, the research team based out of Tarbiat Modares University in Tehran, Iran, saw an increase in the levels and activity of an enzyme that degrades NAD+ called CD38 in a brain region vulnerable to epileptogenesis — the hippocampus, which is linked to learning and memory. The study goes on to show that these changes in NAD+ and CD38 levels are linked to dysregulated calcium signaling, which is fundamental to the excitability of brain cells and may explain epileptogenesis.
Taken together, these results revealed that CD38-induced elevation of cell calcium levels could be a key damage-causing event in epilepsy and present targets for developing an effective treatment strategy to combat epileptogenesis.
NAD+ deficiency is an important factor in several neurological disorders, including epilepsy. Interestingly, NAD+ treatment can suppress epileptogenesis by reducing cell death in the hippocampus of mice. So, investigating how NAD+ becomes deficient may prove helpful in developing a comprehensive approach for the effective treatment of neurological disorders like epilepsy.
Khodaverdiana and colleagues dived into this and found that seizures in rodents induced by electrical overstimulation caused a significant decrease in NAD+ levels of cells in the hippocampus. When they looked at the levels of proteins involved in the consumption and degradation of NAD+ to find the culprits behind this NAD+ decline during epilepsy, the only protein they found to be altered was CD38, suggesting a key role for CD38 in the progression of epileptogenesis.
Not only is CD38 an NAD+ degrading enzyme, but it also plays a role in controlling intracellular calcium levels, which are critical for cell-to-cell communication in the brain and many other tissues. Too much calcium can lead to overexcitability of brain cells, which leads to brain damage.
CD38 plays a crucial role in controlling calcium levels by producing a tiny compound called cyclic ADP ribose (cADPR) from NAD+. Typically sitting on the outer membrane of cells with its enzymatic component facing the outside of the cell, activated CD38 consumes NAD+ and spits out, among other things, cADPR that can then be used by the cell to activate certain complexes, including calcium channels.
Several studies have shown that cADPR is involved in the activation of a molecular complex with channels that shuttle calcium critical for intercell communication in the hippocampus and other areas that have been linked to seizures. This complex consists of ryanodine receptors (Ryr), which release calcium stored up in a cellular structure called the endoplasmic reticulum into the fluid in the cell body (cytoplasm) of brain cells, and a protein called Fkbp-12.6 that is essential for regulating the activity of these ryanodine receptors. When Fkbp-12.6 is bound to the complex, the ryanodine receptors are shut down. But when it dissociates from the complex, the ryanodine receptors get activated.
What Khodaverdiana and colleagues found was that although there were no changes in ryanodine receptor levels in epileptogenesis, they saw a 20% reduction of Fkbp-12.6 protein levels. Khodaverdiana and colleagues think that increased levels of CD38 and decreased levels of Fkbp-12.6 might cause excessive stimulation of ryanodine receptors, which blasts brain cells with excitability and epilepsy that ultimately lead to their death.
This study suggests that NAD+ decline and calcium elevation may be critical to the development of epilepsy and epileptogenesis. So, CD38, cADPR signaling proteins like Fkbp12.6, and calcium channels like ryanodine receptors appear to be potential targets for epilepsy treatment. These findings need to be first confirmed in humans before setting out on targeting these proteins to treat epileptogenesis.