Novel Co-crystal of Pentoxifylline and Protocatechuic Acid Relieves Allodynia in Rat Models of Peripheral Neuropathic Pain and CRPS by Alleviating Local Tissue Hypoxia

Abstract

Local tissue ischemic hypoxia is a peripheral process that can be targeted with topical treatment to alleviate pain under chronic pain conditions such as complex regional pain syndrome (CRPS) and peripheral neuropathic pain. We recently reported three novel salts and a co-crystal composed of vasoactive agents and antioxidant nutraceuticals, all of which produced potent topical anti-allodynic effects in the chronic postischemic pain (CPIP) rat model of CRPS. One of the products, pentx-pca, is a co-crystal synthesized from pentoxifylline (pentx) and protocatechuic acid (pca). Pentx-pca exhibited potent topical anti-allodynic effects in CPIP and rats with chronic constriction injury of the sciatic nerve exceeding effects produced individually by pentx and pca. We hypothesized that the anti-allodynic effects of pentx-pca in CPIP rats were due to its impact on local tissue oxygenation and subsequent oxygen-dependent mitochondrial respiration. Percutaneous tissue oxygen saturation (SaO2) measurements taken from the hind paw of the CPIP rats revealed that anti-allodynic doses of topical pentx-pca increased local tissue SaO2. Moreover, assessment of the oxygen-dependent mitochondrial function using a triphenyl tetrazolium chloride assay revealed that mitochondrial dysfunction significantly declined in the plantar muscle collected from CPIP rats topically treated with anti-allodynic doses of pentx-pca as compared to vehicle-treated CPIP rats. Furthermore, time-dependent resolution of plantar muscle mitochondrial dysfunction, that occurred in the CPIP rats at 6-week post procedure, paralleled the loss of the anti-allodynic response to topical treatment with pentx-pca. Our results indicated that pentx-pca produced potent anti-allodynic effects in the CPIP rat model of CRPS by alleviating peripheral tissue ischemia/hypoxia and downstream hypoxia-driven mitochondrial dysfunction.