Restorative potential of dopaminergic grafts in presence of antioxidants in rat model of Parkinson's disease.
Free radical mediated damage has been reported to contribute significantly towards low survival (5-10%) of grafted dopaminergic neurons, post transplantation. In the present study, an attempt has been made to explore the neuroprotective potential of the combination of two major antioxidants ascorbic acid (AA) and glutathione (GSH) on ventral mesencephalic cells (VMC) and nigral dopamine (DA) neurons when co-transplanted together with VMC in rat model of Parkinson's disease (PD). GSH and AA have been reported to act co-operatively in the conditions of oxidative stress thereby helping in maintaining the cellular GSH/GSSG redox status. Functional recovery was assessed 12 weeks post transplantation, where a significant restoration (p<0.001) in d-amphetamine induced circling behavior (62%), spontaneous locomotor activity (SLA; 64%), dopamine-D2 receptor binding (63%), dopamine (65%) and 3,4-dihydroxy phenyl acetic acid (DOPAC) level (64%) was observed in co-transplanted animals as compared to lesioned and VMC alone grafted rats. VMC and GSH+AA co-transplanted animals exhibited a significantly higher surviving TH-immunoreactive (TH-ir) neurons number (p<0.01), TH-ir fibers outgrowth (p<0.05) in striatal graft and TH-ir neurons in substantia nigra pars compacta (SNpc) (p<0.01), as compared to VMC alone transplanted rats. An attempt was made to further confirm our in vivo observations through in vitro experiments where following in vitro exposure to 6-OHDA, a higher cell survival (p<0.01), TH-ir cell counts (p<0.001) and DA and DOPAC levels (p<0.01) were also observed in 8-day-old VMC culture in presence of GSH+AA as compared to VMC cultured in absence of antioxidants. The results suggest that GSH+AA when co-transplanted with VMC provide higher restoration probably by increasing the survival of grafted VMC and simultaneously supporting nigral TH-immunopositive neurons in rat model of PD.
Agrawal
A K
AK
Developmental Toxicology Division, Industrial Toxicology Research Centre, Post Box 80, M.G. Marg, Lucknow 226 001, India. aka33@rediffmail.com
Chaturvedi
R K
RK
Shukla
S
S
Seth
K
K
Chauhan
S
S
Ahmad
A
A
Seth
P K
PK
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D016380:Brain Tissue Transplantation / Q000502:physiology*; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000637:transplantation*; D020734:Parkinsonian Disorders / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation*
D000975:Antioxidants; D015102:3,4-Dihydroxyphenylacetic Acid; D005978:Glutathione; D001205:Ascorbic Acid; D003913:Dextroamphetamine; D004298:Dopamine