Selective scavenging of intra-mitochondrial superoxide corrects diclofenac-induced mitochondrial dysfunction and gastric injury: A novel gastroprotective mechanism independent of gastric acid suppression.
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat multiple inflammatory diseases and pain but severe gastric mucosal damage is the worst outcome of NSAID-therapy. Here we report that mitoTEMPO, a mitochondrially targeted superoxide (O2-) scavenger protected as well as healed gastric injury induced by diclofenac (DCF), the most commonly used NSAID. Common existing therapy against gastric injury involves suppression of gastric acid secretion by proton pump inhibitors and histamine H2receptor antagonists; however, dyspepsia, vitamin B12 deficiency and gastric microfloral dysbalance are the major drawbacks of acid suppression. Interestingly, mitoTEMPO did not inhibit gastric acid secretion but offered gastroprotection by preventing DCF-induced generation of O2-due to mitochondrial respiratory chain failure and by preventing mitochondrial oxidative stress (MOS)-mediated mitopathology. MitoTEMPO even restored DCF-stimulated reduced fatty acid oxidation, mitochondrial depolarization and bioenergetic crisis in gastric mucosa. MitoTEMPO also prevented the activation of mitochondrial pathway of apoptosis and MOS-mediated proinflammatory signaling through NF-κB by DCF. Furthermore, mitoTEMPO when administered in rats with preformed gastric lesions expedited the healing of gastric injury and the healed stomach exhibited its normal physiology as evident from gastric acid and pepsin secretions under basal or stimulated conditions. Thus, in contrast to the existing antiulcer drugs, mitochondrially targeted O2-scavengers like mitoTEMPO may represent a novel class of gastroprotective molecules that does not affect gastric acid secretion and may be used in combination with DCF, keeping its anti-inflammatory action intact, while reducing its gastrodamaging effects.
Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, West Bengal, India.
Somnath
S
Mazumder
Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, West Bengal, India.
Rudranil
R
De
Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, West Bengal, India.
Souvik
S
Sarkar
Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, West Bengal, India.
Asim Azhar
AA
Siddiqui
Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, West Bengal, India.
Shubhra Jyoti
SJ
Saha
Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, West Bengal, India.
Chinmoy
C
Banerjee
Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, West Bengal, India.
Mohd Shameel
MS
Iqbal
Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, West Bengal, India.
Shiladitya
S
Nag
Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, West Bengal, India.
Subhashis
S
Debsharma
Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, West Bengal, India. Electronic address: ubandyo_1964@yahoo.com.
Uday
U
Bandyopadhyay
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004008:Diclofenac / Q000009:adverse effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D005756:Gastritis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D013481:Superoxides; D004008:Diclofenac
2-Mercapto-1-methylimidazole (PubChem CID: 1349907); Diclofenac (PubChem CID: 5018304); Gastropathy; Indomethacin (PubChem CID: 3715); Inflammation; JC-1 (PubChem CID: 5492929); Lansoprazole (PubChem CID: 3883); MTT (PubChem CID: 64965); Mitochondria; Mitochondrial apoptosis; Mitochondrial metabolism; NSAID; Oligomycin (PubChem CID: 6364620); Oxidative stress; Ranitidine (PubChem CID: 3033332)