Details

Autor(en) / Beteiligte

• Gupta, Sonam
• Goswami, Poonam
• Biswas, Joyshree
• Joshi, Neeraj
• Sharma, Sharad
• Nath, C.
• Singh, Sarika

Titel

6-Hydroxydopamine and lipopolysaccharides induced DNA damage in astrocytes: Involvement of nitric oxide and mitochondria

Ist Teil von

• Mutation research. Genetic toxicology and environmental mutagenesis, 2015-01, Vol.778, p.22-36

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• •6-OHDA/LPS caused increased expression of GFAP and DNA damage in astrocytes.•6-OHDA/LPS treatment caused increased expression of iNOS and nitrite level.•iNOS inhibitor, aminoguanidine attenuates the DNA damage in astrocytes.•6-OHDA/LPS caused mitochondrial impairment and apoptosis in astrocytes.•Nitric oxide has emerged as key player in DNA damage in astrocytes. The present study was conducted to investigate the effect of the neurotoxins 6-hydroxydopamine and lipopolysaccharide on astrocytes. Rat astrocyte C6 cells were treated with different concentration of 6-hydroxydopamine (6-OHDA)/lipopolysaccharides (LPS) for 24h. Both neurotoxins significantly decreased the viability of astrocytes, augmented the expression of inducible nitric oxide synthase (iNOS) and the astrocyte marker – glial fibrillar acidic protein. A significantly decreased mitochondrial dehydrogenase activity, mitochondrial membrane potential, augmented reactive oxygen species (ROS) level, caspase-3 mRNA level, chromatin condensation and DNA damage was observed in 6-OHDA/LPS treated astroglial cells. 6-OHDA/LPS treatment also caused the significantly increased expression of iNOS and nitrite level. Findings showed that 6-OHDA/LPS treatment caused mitochondrial dysfunction mediated death of astrocytes, which significantly involve the nitric oxide. Since we have observed significantly increased level of iNOS along with mitochondrial impairment and apoptotic cell death in astrocytes, therefore to validate the role of iNOS, the cells were co-treated with iNOS inhibitor aminoguanidine (AG, 100μM). Co-treatment of AG significantly attenuated the 6-OHDA/LPS induced cell death, mitochondrial activity, augmented ROS level, chromatin condensation and DNA damage. GFAP and caspase-3 expression were also inhibited with co-treatment of AG, although the extent of inhibition was different in both experimental sets. In conclusion, the findings showed that iNOS mediated increased level of nitric oxide acts as a key regulatory molecule in 6-OHDA/LPS induced mitochondrial dysfunction, DNA damage and apoptotic death of astrocytes.