Sustained relief of trigeminal neuropathic pain by a blood–brain barrier penetrable PPAR gamma agonist

The blood–brain barrier (BBB) and blood–nerve barrier ensure protection of the nervous system but pose a challenge for the treatment of pain since it restricts passage of many therapeutic drugs. Although it is unknown which blood–neural barrier is more relevant, or whether permeabilities are the same for different barriers, we proposed that the inefficiency of thiazolidinedione-type agonists for peroxisome proliferator-activated receptor gamma (PPARɣ) is due to their difficulty in passage through the BBB. We developed a new highly BBB penetrable PPARɣ agonist for the treatment of neuropathic pain, assuming BBB permeability is a rule of thumb to estimate the overall permeability of relevant blood–neural barriers. As an index of brain penetration, the brain–plasma ratio (Kp) of ELB00824 is 5.13, suggesting very high brain bioavailability, which is 58-fold that of pioglitazone. The series of studies presented here indicate that ELB00824 may be the most potent PPARɣ agonist currently known for acute reduction of neuropathic pain in trigeminal nerve in rat and mouse models. Low-dose PPARɣ agonist, ELB00824 (10 mg/kg), effectively decreased neuropathic hypersensitivity in mice and rats at both acute and chronic time points, a dose 100-fold lower than the effective dose (1000 mg/kg, i.p.) of pioglitazone. Comparisons of ELB00824 alone or in combination with gabapentin or carbamazepine are provided. While PPARɣ agonists used to treat Type 2 diabetes produce several adverse side effects, sub-chronic oral toxicity study provided promising results that ELB00824 does not produce any significant short-term toxicity. The study animals of either sex remained alive and healthy with no significant alteration of body weight long term. Toxicity study results obtained were satisfactory, with no significant alterations in any serum biochemistry parameters.