Pharmacologic Overview of Chlorogenic Acid and its Metabolites in Chronic Pain and Inflammation.

BACKGROUND: Natural phenolic compounds in medicinal herbs and dietary plants are antioxidants which play therapeutic or preventive roles in different pathological situations, such as oxidative stress and inflammation. One of the most studied phenolic compounds in the last decade is chlorogenic acid (CGA), which is a potent antioxidant found in certain foods and drinks. OBJECTIVE: This review focuses on the anti-inflammatory and antinociceptive bioactivities of CGA, and the putative mechanisms of action are described. Ethnopharmacological reports related to these bioactivities are also reviewed. MATERIALS AND METHODS: An electronic literature search was conducted by authors up to October 2019. Original articles were selected. RESULTS: CGA has been shown to reduce inflammation and modulate inflammatory and neuropathic pain in animal models. CONCLUSION: The consensus of the literature search was that systemic CGA may facilitate pain management via bolstering antioxidant defenses against inflammatory insults.

The Antinociceptive and Antiinflammatory Properties of 3-furan-2-yl-N-p-tolyl-acrylamide, a Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptors in Mice.

BACKGROUND: Positive allosteric modulators (PAMs) facilitate endogenous neurotransmission and/or enhance the efficacy of agonists without directly acting on the orthosteric binding sites. In this regard, selective α7 nicotinic acetylcholine receptor type II PAMs display antinociceptive activity in rodent chronic inflammatory and neuropathic pain models. This study investigates whether 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a new putative α7-selective type II PAM, attenuates experimental inflammatory and neuropathic pains in mice. METHODS: We tested the activity of PAM-2 after intraperitoneal administration in 3 pain assays: the carrageenan-induced inflammatory pain, the complete Freund adjuvant-induced inflammatory pain, and the chronic constriction injury-induced neuropathic pain in mice. We also tested whether PAM-2 enhanced the effects of the selective α7 agonist choline in the mouse carrageenan test given intrathecally. Because the experience of pain has both sensory and affective dimensions, we also evaluated the effects of PAM-2 on acetic acid-induced aversion by using the conditioned place aversion test. RESULTS: We observed that systemic administration of PAM-2 significantly reversed mechanical allodynia and thermal hyperalgesia in inflammatory and neuropathic pain models in a dose- and time-dependent manner without motor impairment. In addition, by attenuating the paw edema in inflammatory models, PAM-2 showed antiinflammatory properties. The antinociceptive effect of PAM-2 was inhibited by the selective competitive antagonist methyllycaconitine, indicating that the effect is mediated by α7 nicotinic acetylcholine receptors. Furthermore, PAM-2 enhanced the antiallodynic and antiinflammatory effects of choline, a selective α7 agonist, in the mouse carrageenan test. PAM-2 was also effective in reducing acetic acid-induced aversion in the conditioned place aversion assay. CONCLUSIONS: These findings suggest that the administration of PAM-2, a new α7-selective type II PAM, reduces the neuropathic and inflammatory pain sensory and affective behaviors in the mouse. Thus, this drug may have therapeutic applications in the treatment and management of chronic pain.

Antinociceptive effect of chlorogenic acid in rats with painful diabetic neuropathy.

The present study aimed to evaluate possible antinociceptive effects of chlorogenic acid in streptozotocin-induced diabetic neuropathic pain in rats. Chlorogenic acid (100 mg/kg) was administered daily for 14 days. Our study showed for the first time that both single and chronic chlorogenic acid treatments produced significant antinociceptive effects in diabetic rats. In contrast, single dose of chlorogenic acid showed no signs of an antinociceptive effect, but chronic treatment exerted antinociceptive potential in nondiabetic rats. Additionally, chronic treatment effectively reduced hyperglycemia that induced by diabetes. In conclusion, chlorogenic acid has beneficial effects for the management of diabetic neuropathic pain.

The protective effect of ClinOleic against post-surgical adhesions.

BACKGROUND: Although the English-language literature is full of studies about post-surgical adhesions, no definitive method has yet been identified to prevent them. The goal of this study was to investigate the effect of ClinOleic on reducing post-surgical adhesion formation. METHODS: Surgery was performed on 40 adult female Sprague-Dawley rats that were randomly assigned to receive either intraperitoneal ClinOleic, which was used to mimic chyle (ClinOleic group), soybean oil (soybean oil group), olive oil (olive oil group), or 0.9% NaCl suspension (control group). All rats underwent laparotomy, side-wall and cecal abrasion, and primary closure. On the 30th day following surgery, rats were sacrificed and examined using the Majuzi adhesion classification and histopathological grading scales. RESULTS: The adhesion and histopathological scores of the ClinOleic group were significantly lower compared to the control group (0.9% NaCl) (p<0.05). A statistically significant decrease in fibrosis was observed in the soybean and olive oil groups when compared to the control group (p<0.05). However, the adhesion grades of the ClinOleic, soybean and olive oil groups were comparable. We did not observe any post-surgical adhesions in the ClinOleic group. CONCLUSION: The parenteral nutrition solution ClinOleic may be an effective and readily available agent for the prevention of post-surgical adhesions.

Effects of systemic chlorogenic acid on random-pattern dorsal skin flap survival in diabetic rats.

There has been considerable interest in understanding the effects of antioxidants in flap survival during diabetes. Previous studies showed that chlorogenic acid (CGA) exhibits potent antioxidant effects. We aimed to determine the effects of systemic CGA treatment on skin flap survival in an experimental random-pattern dorsal skin flap model in diabetic rats. Twenty-eight male Wistar rats were divided into four groups: phosphate buffered saline (PBS)-treated or CGA-treated nondiabetic rats, PBS-treated or CGA-treated diabetic rats. Diabetes was induced by streptozotocin (45 mg/kg). Caudally based bipedicled dorsal skin flaps were elevated. CGA (100 mg/kg) or PBS (mL/kg; as vehicle) was administered intraperitoneally once daily. On postoperative day 7, flap survival, regional blood perfusion and microangiography were evaluated. The malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and nitric oxide (NO) levels were evaluated from the flap tissue. Capillary density and vascular endothelial growth factor (VEGF) expression were assessed. Harmful effects of diabetes on flap survival were observed. CGA attenuated these effects and allowed greater survival and blood perfusion. CGA decreased MDA and NO levels and increased GSH and SOD levels. CGA elevated capillary density and VEGF expression. This study showed that peripherally administered CGA significantly improved flap survival in diabetic and nondiabetic rats.

Antihyperalgesic activity of chlorogenic acid in experimental neuropathic pain.

Chlorogenic acid (CGA) is a natural organic phenolic compound that is found in many plants, fruits and vegetables. CGA has beneficial bioactivities and strong therapeutic effects in inflammatory processes. CGA-rich fractions have analgesic activity but CGA has not been tested previously in neuropathic pain, which results from tissue damage, inflammation or injury of the nervous system. Chronic constrictive nerve injury (CCI) is a peripheral neuropathic pain model which initiates an inflammatory cascade. We aimed to determine possible antihyperalgesic effects of CGA in neuropathic pain. Our study showed for the first time that CGA [50, 100 and 200 mg/kg; intraperitoneally (i.p.)] produced significant dose- and time-dependent antihyperalgesic activity in CCI-induced neuropathic pain. In addition, chronic administration of CGA (100 mg/kg/day; i.p. for 14 days) prevented the development of mechanical hyperalgesia and attenuated CCI-induced histopathological changes. On the other hand, CGA (200 mg/kg) did not affect falling latencies of rats in the rota rod test. Hence, CGA might represent a novel potential therapeutic option for the management of neuropathic pain.