Ibudilast produces anti-allodynic effects at the persistent phase of peripheral or central neuropathic pain in rats: Different inhibitory mechanism on spinal microglia from minocycline and propentofylline

Contribution of intraganglionic CGRP to migraine-like responses in male and female rats

“…Herein, we have shown that blockade of glial cells with minocycline and propentofylline significantly reduced periorbital mechanical allodynia in male rats, reinforcing the idea that glial cells contribute to CGRP effect. However, it is important to point out that both minocycline and propentofylline are non-selective glial inhibitors (19,20). Although we have injected these drugs directly into the TG, at a volume that has been shown not to cause solution spreading to adjacent structures (21,39) and at a dose that has been shown to cause glial cell inhibition (17,19), it is possible that they are modulating different targets.…”

“…On the other hand, propentofylline is a phosphodiesterase inhibitor that has a broad inhibitory action on both microglia and astrocytes, by reducing adenosine uptake and the expression of adenosine receptors (49,50). In contrast to minocycline, it does not affect the expression or hypertrophic morphology of glial cells and seems to exert less influence on release of cytokines (20). Thus, the present data, obtained with two mechanistically different glial inhibitors, does not indicate a conclusive target for these drugs, but allows the suggestion that cooperative interactions between TG glial cells and neurons may contribute to CGRP allodynic actions.…”

“…), minocycline (Sigma-Aldrich, St. Louis, MO, USA) was dissolved in water for injection (100 µg/10 µL) and propentofylline (Santa Cruz Biotech, Dallas, TX, USA) was dissolved in saline (25 µg/10 µL). Doses were selected based on previous studies (13,17–20).…”

T-Cell Activation-Inhibitory Assay to Screen Caloric Restriction Mimetics Drugs for Drug Repositioning

“…Ibudilast was originally developed for the treatment of asthma and dizziness in Japan; however, the drug's application has been considered for various inflammatory diseases, such as multiple sclerosis 17) and neuropathic pain. 18) Recently, an investigational new drug (IND) application for the use of ibudilast against COVID-19 was submitted to the US-FDA (https://www.biospace.com/article/releases/medicinovaannounces-opening-of-investigational-new-drug-application-for-mn-166-ibudilast-for-prevention-of-acute-respiratory-distress-syndrome-in-patients-with-covid-19/).…”

Drug Repurposing to Target Neuroinflammation and Sensory Neuron-Dependent Pain

“…Likely off-target due to high dose [ 117 ] Ibudilast Phosphodiesterase inhibitor (mainly PDE4) Sciatic nerve injury in rats Single intrathecal injection 25 µg Repeated intrathecal injection (25 µg) daily for 4 days from day 11 post-injury Treatment reduces mechanical hypersensitivity after sciatic nerve injury in rats, reduces the numbers of iba1-positive microglia in the spinal cord, and the numbers of pp38-positive cells. Possibly off-target due to high dose Currently in clinical testing [ 63 ] Oxaliplatin-induced neuropathic pain 7.5 mg/kg IP for 3 days, or a single dose before von-Frey-testing reduces oxaliplatin-induced mechanical hypersensitivity in rats. Likely off-target due to high dose [ 62 ] Opioid withdrawal symptoms and opioid-dependent analgesia Ibudilast 50 mg twice daily for 30 days Reduces opioid withdrawal symptoms and increases the analgesic effects of oxycodone in human volunteers diagnosed with opioid dependence [ 64 ] Minocycline Antibiotic (tetracycline) Skin/muscle incision and retraction (SMIR) model 100 µg Ith for 7 days Treatment reduces mechanical allodynia in vivo and reduced the A1/A2 ratio of spinal astrocytes.…”