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

Abstract

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.

Trigeminal neuropathic pain is alleviated by inhibition of Cav3.3 T-type calcium channels in mice

“…Mechanical threshold of the whisker pad area was tested before and after surgery with a modified up/down method using a graded series of von Frey fiber filaments as described previously [ 1 , 4 , 5 ].…”

Building and Testing PPARγ Therapeutic ELB00824 with an Improved Therapeutic Window for Neuropathic Pain

“…There is an interplay between the physical symptoms of pain and its psychological effects involving brain limbic circuitry that are revealed after weeks of persisting pain. Hypersensitivity, anxiety, depression, and even cognitive deficit are measurable in preclinical models [18,27,28,[41][42][43][44][45][46]. These pain-related characteristics closely resemble symptomatology present in many patients with chronic neuropathic pain [41].…”

“…In only a few of the current models does the nerve injury and nociceptive alteration continue, inducing central sensitization and the brain circuitry changes leading to the chronification of pain. Examples of persisting preclinical models include the spared nerve injury models (SNI) [21,22] and the trigeminal nerve tie (CCI-ION, dIoN) [23][24][25] or compression models (TIC, FRICT-ION) [26][27][28]. Persisting increases in levels of cytokines may explain the differences in the persistence of hypersensitivity between acute duration and chronic duration of preclinical models [29].…”

“…The clinical use of PPARγ modulators pioglitazone and rosiglitazone has revealed common adverse effects, however [13]. Toxicity study for our recently developed PPARγ agonist included once-daily treatment of rats for 14 days with ELB00824 (0, 30, 120, 450 mg/kg) [27]. The rats observed daily exhibited no signs of physical, behavioral, food intake, body weight, or water consumption abnormalities.…”

Minimally Invasive Oral Surgery Induction of the FRICT-ION Chronic Neuropathic Pain Model

“…minimally invasive intraoral FRICT-ION approach described here was first used in a recent publication, but we referred to it there as the "TIC" method (Zhang et al, 2019). The FRICT-ION protocol was adapted or modified from our previous trigeminal inflammatory compression (TIC) method where chromic gut suture was aligned along the infraorbital nerve in mice using the more…”