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

Abstract

Effective, non-addictive therapeutics for chronic pain remain a critical need. While there are several potential therapeutics that stimulate anti-inflammatory mechanisms to restore homeostasis in the spinal dorsal horn microenvironment, the effectiveness of drugs for neuropathic pain are still inadequate. The convergence of increasing knowledge about the multi-factorial mechanisms underlying neuropathic pain and the mechanisms of drug action from preclinical studies are providing the ability to create pharmaceuticals with better clinical effectiveness. By targeting and activating the peroxisome proliferator-activated receptor gamma subunit (PPARγ), numerous preclinical studies report pleiotropic effects of thiazolidinediones (TDZ) beyond their intended use of increasing insulin, including their anti-inflammatory, renal, cardioprotective, and oncopreventative effects. Several studies find TDZs reduce pain-related behavioral symptoms, including ongoing secondary hypersensitivity driven by central sensitization. Previous studies find increased PPARγ in the spinal cord and brain regions innervated by incoming afferent nerve endings after the induction of neuropathic pain models. PPARγ agonist treatment provides an effective reduction in pain-related behaviors, including anxiety. Data further suggest that improved brain mitochondrial bioenergetics after PPARγ agonist treatment is a key mechanism for reducing hypersensitivity. This review emphasizes two points relevant for the development of better chronic pain therapies. First, employing neuropathic pain models with chronic duration is critical since they can encompass the continuum of molecular and brain circuitry alterations arising over time when pain persists, providing greater relevance to clinical pain syndromes. Assisting in that effort are preclinical models of chronic trigeminal pain syndromes. Secondly, considering the access to nerve and brain neurons and glia across the blood–brain barrier is important. While many therapies have low brain penetrance, a PPARγ agonist with better brain penetrance, ELB00824, has been developed. Purposeful design and recent comparative testing indicate that ELB00824 is extraordinarily efficient and efficacious. ELB00824 provides greatly improved attenuation of pain-related behaviors, including mechanical hypersensitivity, anxiety, and depression in our chronic trigeminal nerve injury models. Physiochemical properties allowing significant brain access and toxicity testing are discussed.

Rapid Generation and Molecular Docking Analysis of Single-Chain Fragment Variable (scFv) Antibody Selected by Ribosome Display Targeting Cholecystokinin B Receptor (CCK-BR) for Reduction of Chronic Neuropathic Pain

“…Remarkably, the hypersensitivity persists in untreated mice with the FRICT-ION chronic neuropathic pain model through 100 days. In addition to being a great model of craniofacial neuropathic pain, FRICT-ION is the only model of trigeminal neuralgia since it is responsive to carbamazepine [ 43 ]. The reduction of hypersensitivity at 1 week prevents the development of many of the anxiety and depression measures tested here with the zero maze and the light/dark tests.…”

Prospects of antidiabetic drugs in the treatment of neurodegenerative disease

“…To resolve this issue, a PPARγ agonist exhibiting superior brain permeability, ELB00824, was formulated; this drug exhibits substantial efficacy in a chronic trigeminal nerve injury model. [103] PPARγ agonists promote the formation of a PPARγ heterodimeric complex with nuclear receptor-9-cisretinoic acid (RXR) that binds to PGC-1α and subsequently regulates the transcription of genes related to mitochondrial biogenesis and oxidative stress. [88] PGC-1α promotes the expression of downstream target genes involved in mitochondrial biogenesis, such as mitochondrial transcription factor A (TFAM), nuclear respiratory factor 1 (NRF-1), and NRF-2 (Figure 2).…”

“…Nevertheless, the extent of its BBB penetration remains controversial. To resolve this issue, a PPARγ agonist exhibiting superior brain permeability, ELB00824, was formulated; this drug exhibits substantial efficacy in a chronic trigeminal nerve injury model [103] …”

The Impact of P-Glycoprotein on Opioid Analgesics: What’s the Real Meaning in Pain Management and Palliative Care?

“…Many painful conditions may be associated with neuropathic components, so that 7-10% of the general population is believed to suffer from neuropathic pain [125]. Structural changes and permeability of the blood-spinal cord barrier (BSCB) [126], the blood nerve barrier [127], and the BBB [128] may be crucial factors for development of neuropathy in several pathological states, ranging from diabetic neuropathy [129], trigeminal neuralgia [130], radiculopathies [131], and migraine [66,132]. Particularly, abnormal expression of BBB proteins, namely laminin and ZO-1, has been described during cortical spreading depression (CSD), the latter typically occurring during migraine attacks [66].…”