Proof-of-concept of drug resistance hypotheses
As suggested by Sisodiya (2003), at least four criteria must be satisfied for a proposed drug-resistance mechanism of epilepsy to be accepted; the mechanism must 1) be detectable in epileptogenic brain tissue, 2) have appropriate functionality, 3) be active in drug resistance (and not be an epiphenomenon), and 4) drug resistance should be affected when the mechanism is overcome. These criteria are based on the famous Koch’s postulates, which were originally proposed by Robert Koch in 1890 to establish a causal relationship between a bacterium and a disease.
| Drug-resistance hypothesis in epilepsy | Detectable in brain (or peripheral) tissues of nonresponders | Appropriate functionality | Active in ASD resistance | Resistance reversed when mechanism is overcome |
|---|---|---|---|---|
| Target hypothesis | + (rat) | + (rat) | ? (rat) | ? (rat) |
| + (human) | + (human) | ? (human) | ? (human) | |
| Transporter hypothesis | + (rat) | + (rat) | + (rat) | + (rat) |
| + (human) | + (human) | + (human) | ? (human) | |
| Pharmacokinetic hypothesis | - (rat) | - (rat) | ? (rat) | ? (rat) |
| + (human) | ? (human) | ? (human) | ? (human) | |
| Neural network hypothesis | + (rat) | ? (rat) | ? (rat) | ? (rat) |
| + (human) | ? (human) | ? (human) | + (human) | |
| Intrinsic severity hypothesis | + (rat)a | ? (rat) | ? (rat) | ? (rat) |
| + (human)a | ? (human) | ? (human) | ? (human) | |
| Gene variant hypothesis | + (rat) | + (rat) | ? (rat) | ? (rat) |
| + (human) | + (human) | +/? (human) | +/? (human) | |
| Epigenetic hypothesis | + (rat/mouse) | +/? (rat/mouse) | +/? (rat/mouse) | +/? (rat/mouse) |
| + (human) | ? (human) | ? (human) | ? (human) | |
| Neuroinflammation/blood-brain barrier | + (rat, mouse) | + (rat) | + (rat) | + (rat) |
| + (human) | ? (human) | ? (human) | ? (human) |
↵a Increased seizure frequency/density compared with ASD responders.