minocycline and Edema

Minocycline is a semi-synthetic antimicrobial agent with claimed anti-inflammatory properties reported from different experimental models. This study was aimed to evaluate the anti-inflammatory effects of minocycline, compared to the actions of two common anti-inflammatory agents, on lipopolysaccharide (LPS)-induced paw oedema through some clinical, histopathological, haematological and molecular analyses. Forty-eight rats were divided into eight groups (n = 6). In control group (Ctrl), each animal was injected with normal saline into its sub-plantar region of hind paw. In groups 2-7, hind paw oedema was induced by injection of LPS. One hour before injections, groups 1 (Ctrl) and 2 (LPS) were treated orally with distilled water, 3 and 4 with methylprednisolone (Pred) and meloxicam (Melo) and 5-7 with minocycline in doses of 50, 150 and 450 mg/kg (M50, M150 and M450, respectively). The 8th group (MC) was given minocycline (150 mg/kg) orally and normal saline was injected into sub-plantar region. Paw swelling and body temperature were assessed at 0, 2, 4, 6 and 24 h post-injections. At 24 h, samples of blood and liver, kidney, spleen and hind paw tissues were taken for haematological and histopathological examinations. Some samples of the paw were also obtained for molecular analysis of some inflammatory-related cytokines at mRNA level. Paw swelling and body temperature increased in all LPS-injected groups 2 h post-injection. In LPS group, they remained significantly increased up to 24 h; however, these parameters decreased to normal in Pred, Melo and all minocycline groups. The histological findings showed mild-to-moderate signs of inflammation in tissue samples of groups 2-6, but not in group M450. Additionally, gene expression of pro-inflammatory cytokines (IL-1β and IL-6) increased significantly in LPS group compared to other groups. In conclusion, this study supports the role of minocycline as an anti-inflammatory agent with effects comparable to those of meloxicam and methylprednisolone.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Edema; Inflammation; Lipopolysaccharides; Meloxicam; Methylprednisolone; Minocycline; Rats; Saline Solution

Tibia fracture in rodents induces substance P (SP)-dependent keratinocyte activation and inflammatory changes in the hindlimb, similar to those seen in complex regional pain syndrome (CRPS). In animal pain models spinal glial cell activation results in nociceptive sensitization. This study tested the hypothesis that limb fracture triggers afferent C-fiber SP release in the dorsal horn, resulting in chronic glial activation and central sensitization. At 4 weeks after tibia fracture and casting in rats, the cast was removed and hind paw allodynia, unweighting, warmth, and edema were measured, then the antinociceptive effects of microglia (minocycline) or astrocyte (L-2-aminoadipic acid (LAA)) inhibitors or an SP receptor antagonist (LY303870) were tested. Immunohistochemistry and PCR were used to evaluate microglial and astrocyte activation in the dorsal horn. Similar experiments were performed in intact rats after brief sciatic nerve electric stimulation at C-fiber intensity. Microglia and astrocytes were chronically activated at 4 weeks after fracture and contributed to the maintenance of hind paw allodynia and unweighting. Furthermore, LY303870 treatment initiated at 4 weeks after fracture partially reversed both spinal glial activation and nociceptive sensitization. Similarly, persistent spinal microglial activation and hind paw nociceptive sensitization were observed at 48 h after sciatic nerve C-fiber stimulation and this effect was inhibited by treatment with minocycline, LAA, or LY303870. These data support the hypothesis that C-fiber afferent SP signaling chronically supports spinal neuroglial activation after limb fracture and that glial activation contributes to the maintenance of central nociceptive sensitization in CRPS. Treatments inhibiting glial activation and spinal inflammation may be therapeutic for CRPS.

Topics: 2-Aminoadipic Acid; Animals; Anti-Inflammatory Agents; Complex Regional Pain Syndromes; Disease Models, Animal; Edema; Excitatory Amino Acid Antagonists; Hyperalgesia; Male; Minocycline; Neuroglia; Nociception; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Signal Transduction; Spinal Cord; Substance P; Tibial Fractures; Time Factors

It is well known that spinal glia plays a key role in the pathogenesis of pain. The present study was designed to determine the roles of spinal microglia in bee venom-induced persistent spontaneous nociception (PSN), mechanical hyperalgesia and inflammation. We determined the effects of microglia inhibitor minocycline on BV-induced PSN, mechanical hyperalgesia and inflammatory swelling. Pre-treatment with intrathecal administration of minocyline at different doses significantly inhibited BV-induced PSN and mechanical hyperalgesia, but had no effect on BV-induced inflammatory swelling. These data suggest that the activation of spinal microglia may play a key role in BV-induced nociception, but not inflammation.

Topics: Animals; Bee Venoms; Edema; Hyperalgesia; Inflammation; Injections, Spinal; Male; Microglia; Minocycline; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Spinal Cord; Touch

Hemorrhagic transformation is an important complication of acute ischemic stroke, particularly in diabetic patients receiving thrombolytic treatment with tissue plasminogen activator, the only approved drug for the treatment of acute ischemic stroke. The objective of the present study was to determine the effects of acute manipulation of potential targets for vascular protection [i.e., NF-κB, peroxynitrite, and matrix metalloproteinases (MMPs)] on vascular injury and functional outcome in a diabetic model of cerebral ischemia. Ischemia was induced by middle cerebral artery occlusion in control and type 2 diabetic Goto-Kakizaki rats. Treatment groups received a single dose of the peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III), the nonspecific NF-κB inhibitor curcumin, or the broad-spectrum MMP inhibitor minocycline at reperfusion. Poststroke infarct volume, edema, hemorrhage, neurological deficits, and MMP-9 activity were evaluated. All acute treatments reduced MMP-9 and hemorrhagic transformation in diabetic groups. In addition, acute curcumin and minocycline therapy reduced edema in these animals. Improved neurological function was observed in varying degrees with treatment, as indicated by beam-walk performance, modified Bederson scores, and grip strength; however, infarct size was similar to untreated diabetic animals. In control animals, all treatments reduced MMP-9 activity, yet bleeding was not improved. Neuroprotection was only conferred by curcumin and minocycline. Uncovering the underlying mechanisms contributing to the success of acute therapy in diabetes will advance tailored stroke therapies.

Topics: Animals; Curcumin; Diabetes Mellitus, Type 2; Edema; Hemorrhage; Infarction, Middle Cerebral Artery; Locomotion; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Metalloporphyrins; Minocycline; Neuroprotective Agents; NF-kappa B; Peroxynitrous Acid; Rats; Rats, Mutant Strains; Rats, Wistar

Minocycline (Mino) and doxycycline (Dox) are second generation tetracyclines known to present several other effects, which are independent from their antimicrobial activities. We studied in a comparative way the anti-inflammatory effects of Mino and Dox, on acute models of peripheral inflammation in rodents (formalin test and peritonitis in mice, and carrageenan-induced paw oedema in rats). Immunohistochemical assays for TNF-alpha and iNOS in rat paws of carrageenan-induced oedema were also carried out as well as in vitro assays for myeloperoxidase (MPO) and lactate dehydrogenase (LDH). Furthermore, antioxidant activities were evaluated by the DPPH assay.. In the formalin test although Mino and Dox (1, 5, 10 and 25 mg/kg, i.p.) inhibited the first phase, they acted predominantly on the second phase of the test, where inhibition of the licking time close to 80% were observed. Mino and Dox were very efficacious in reducing the carrageenan-induced paw oedema in rats (10, 25 and 50 mg/kg, i.p.) and carrageenan-induced leucocyte migration (1 and 5 mg/kg, i.p.) to mice peritoneal cavities. Besides, they also significantly inhibited MPO and LDH releases at doses ranging from 0.001 to 1 μg/ml. Thus, in general, the anti-inflammatory activity of Dox was higher as compared to that of Mino, although the radical scavenging activity of Mino was of a magnitude 10 times higher.. Our data indicate that anti-inflammatory and antioxidant effects, involve the inhibition of iNOS and TNF-alpha, among other properties, and these encourage clinical studies of these compounds for new therapeutic applications, especially those were inflammation plays a role.

Topics: alpha-Tocopherol; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biphenyl Compounds; Carrageenan; Cell Movement; Doxycycline; Edema; Formaldehyde; Inflammation; L-Lactate Dehydrogenase; Male; Mice; Mice, Inbred Strains; Minocycline; Neutrophils; Nitric Oxide Synthase Type II; Oxidation-Reduction; Pain; Pain Measurement; Peritonitis; Peroxidase; Picrates; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

The present study investigated whether spinal astrocyte and microglia were activated in Buthus martensi Karch (BmK) venom-induced rat pain-related behaviors. The results showed that glial fibrillary acidic protein (GFAP) immunoreactivity indicative astrocyte activation in bilateral spinal cord started to increase by day 3, peaked at day 7 and gradually reversed at day 14 following intraplantar injection of BmK venom. Western blotting analysis confirmed GFAP expression was up-regulated by BmK venom. In contrast, bilateral spinal increase of OX-42 immunoreactivity indicative of microglial activation began at 4h peaked at day 1 and gradually reversed by days 3 to 7 after the administration of BmK venom. Pretreatment with either intrathecal injection of fluorocitrate or intraperitonial injection of minocycline, and two glial activation inhibitors, suppressed the spontaneous nociceptive responses, and prevented the primary thermal and bilateral mechanical hyperalgesia induced by BmK venom. The post-treatment with fluorocitrate or minocycline could not affect the mechanical hyperalgesia. Moreover, minocycline partially inhibited BmK venom-induced spinal c-Fos expression but lack of effects on BmK venom-induced paw edema. Taken together, the current study demonstrated that spinal astrocyte and microglial activation may contribute to BmK venom-induced rat pain-related behaviors. Thus, spinal glia may represent novel targets for effective treatment of pain syndrome associated with scorpion envenomation.

Topics: Analgesics, Non-Narcotic; Animals; Astrocytes; Behavior, Animal; Biomarkers; Citrates; Drug Administration Schedule; Edema; Glial Fibrillary Acidic Protein; Hyperalgesia; Macrophage-1 Antigen; Male; Microglia; Minocycline; Nociceptors; Organ Specificity; Pain; Pain Measurement; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Scorpion Stings; Scorpion Venoms; Scorpions; Spinal Cord; Time Factors

Many in vitro and fewer in vivo studies have shown that tetracyclines present anti-inflammatory activity. We investigated if a novel non-antibacterial, non-chelating hydroxypyrazoline derivative of minocycline, 12S-hydroxy-1,12-pyrazolinominocycline (PMIN), also induced antinociceptive and anti-inflammatory effects.. Antibacterial effects against a minocycline-sensitive Staphylococcus aureus strain were evaluated by applying a cylinder-plate agar diffusion technique. Antibacterial effects of diluted serum from mice pre-treated with minocycline or PMIN were also evaluated. Ca2+ binding activity was assessed by spectrophotometry. Formalin-induced nociceptive responses and carrageenan-induced paw oedema were evaluated in mice. The rota-rod apparatus was used to evaluate motor coordination.. Minocycline, but not PMIN, inhibited bacterial growth. Serum from mice treated with minocycline, but not with PMIN, also induced such an effect. The UV absorption spectrum of solutions of minocycline, but not those of PMIN, was markedly changed in the presence of Ca2+. Minocycline or PMIN inhibited both phases of formalin-induced nociception and carrageenan-induced paw oedema. It is unlikely that antinociception resulted from lack of motor coordination, as tetracycline did not impair the performance of mice on the rotating rod.. These results indicate that inhibition of nociception and oedema by tetracyclines is neither necessarily linked to antibacterial nor to Ca2+ chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the treatment of painful and inflammatory diseases, as its lack of antibacterial and Ca2+ chelating activities might confer greater safety over conventional tetracyclines.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Calcium; Cations, Divalent; Chelating Agents; Edema; Male; Mice; Microbial Sensitivity Tests; Minocycline; Molecular Structure; Motor Activity; Pain; Pain Measurement; Pyrazoles; Rotarod Performance Test; Staphylococcus aureus

Tetracyclines induce anti-inflammatory effects unrelated to their antimicrobial activities. We investigated the effect induced by minocycline and doxycycline in models of nociceptive and inflammatory pain, edema, fever, cell migration and formation of fibrovascular tissue, as these effects have not been fully investigated. Tetracyclines were administered via intraperitoneal route 1 h before the tests. Minocycline and doxycycline (100 mg/kg) inhibited the second phase of the formalin-induced nociceptive response in mice. Doxycycline (100 mg/kg) also inhibited the first phase. The nociceptive response induced by phorbol 12,13-didecanoate (PDD) in mice was inhibited by doxycycline (100 mg/kg). Furthermore, carrageenan-induced mechanical allodynia in rats was inhibited by doxycycline and minocycline (50 or 100 mg/kg). However, they did not enhance the latency in the hot-plate test. It is unlikely that antinociception resulted from motor incoordination or muscle relaxing effect, as both tetracyclines (100 mg/kg) did not impair the motor activity of mice in the rota-rod test. Doxycycline (50 or 100 mg/kg) or minocycline (50 or 100 mg/kg) inhibited carrageenan-induced paw edema in rats. However, only minocycline (100 mg/kg) inhibited PDD-induced edema. Carrageenan-induced leukocyte migration into the peritoneal cavity of rats was inhibited by both tetracyclines (100 mg/kg). Endotoxin-induced fever in rats was also inhibited by doxycycline (50 or 100 mg/kg) or minocycline (100 mg/kg). Finally, formation of fibrovascular tissue induced by subcutaneous implant of a cotton pellet in mice was inhibited by a 6-day administration of both tetracyclines (50 or 100 mg/kg day). Concluding, this study clearly shows the antinociceptive and anti-inflammatory activities of these second-generation tetracyclines.

Topics: Analgesics; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Carrageenan; Doxycycline; Edema; Fever; Formaldehyde; Hot Temperature; Lipopolysaccharides; Male; Mice; Minocycline; Motor Activity; Pain; Phorbol Esters; Rats; Rats, Wistar

It has been demonstrated that spinal microglial activation is involved in formalin-induced pain and that minocycline, an inhibitor of microglial activation, attenuate behavioral hypersensitivity in neuropathic pain models. We investigated whether minocycline could have any anti-nociceptive effect on inflammatory pain, after intraperitonial administration of minocycline, 1 h before formalin (5%, 50 microl) injection into the plantar surface of rat hindpaw. Minocycline (15, 30, and 45 mg/kg) significantly decreased formalin-induced nociceptive behavior during phase II, but not during phase I. The enhancement in the number of c-Fos-positive cells in the L4-5 spinal dorsal horn (DH) and the magnitude of paw edema induced by formalin injection during phase II were significantly reduced by minocycline. Minocycline inhibited synaptic currents of substantia gelatinosa (SG) neurons in the spinal DH, whereas membrane electrical properties of dorsal root ganglion neurons were not affected by minocycline. Analysis with OX-42 antibody revealed the inhibitory effect of minocycline on microglial activation 3 days after formalin injection. These results demonstrate the anti-nociceptive effect of minocycline on formalin-induced inflammatory pain. In addition to the well-known inhibitory action of minocycline on microglial activation, the anti-edematous action in peripheral tissue, as well as the inhibition of synaptic transmission in SG neurons, is likely to be associated with the anti-nociceptive effect of minocycline.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Edema; Electrophysiology; Formaldehyde; Genes, fos; Hindlimb; Inflammation; Injections, Intraperitoneal; Male; Minocycline; Pain; Rats; Rats, Sprague-Dawley; Spinal Cord

Topics: Administration, Topical; Anti-Bacterial Agents; Anti-Infective Agents; Diagnosis, Differential; Edema; Erythema; Facial Dermatoses; Humans; Male; Metronidazole; Middle Aged; Minocycline; Syndrome; Time Factors; Treatment Outcome

Minocycline has been reported to exert neuroprotection through inhibition of inflammatory processes and of mitochondrial cell death pathway. To further characterize the neuroprotective effect of minocycline, we determined its efficacy in different neuronal damage paradigms involving inflammation or mitochondrial dysfunction. In transient global ischaemia in gerbils, minocycline reduced hippocampal neuronal damage measured by peripheral type benzodiazepine binding sites density, a marker of microglial activation. The antiinflammatory properties of minocycline were confirmed on the model of carrageenan-induced paw oedema in rats. The use of two experimental animal models involving administration of mitochondrial toxins inhibiting a different complex of the mitochondrial respiratory chain permitted the exploration of the mitochondrial impact of minocycline. Although minocycline exhibited a marked efficacy in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP; complex I inhibitor)-induced neurotoxicity in mice, it was ineffective in malonate (complex II inhibitor)-induced striatal lesion in rats. In vitro investigations on energized mitochondria isolated from rat liver showed that minocycline (1 microM) did not inhibit the swelling induced by MPP+(1-methyl-4-phenylpyridinium). Moreover, higher concentrations of minocycline induced swelling. From these experiments, the neuroprotective activity of minocycline appears more related to its antiinflammatory activity than to a direct beneficial action on mitochondria.

Topics: Animals; Binding, Competitive; Brain Ischemia; Carrageenan; Corpus Striatum; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Edema; Gerbillinae; Hindlimb; Isoquinolines; Male; Malonates; Mice; Mice, Inbred C57BL; Minocycline; Mitochondrial Swelling; MPTP Poisoning; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Time Factors; Tritium