Potentiation of neurotoxicity of Lathyrus sativus by manganese: alterations in blood-brain barrier permeability.
Environmental factors have been speculated to play an important role in potentiating the neurotoxicity of Lathyrus sativus (LS). Hence, blood-brain barrier permeability and neurotoxicity studies were carried out in manganese- and LS-exposed animals. Dietary feeding of LS (80%) plus Mn (0.4 mg/100 g diet) for 90 days to guinea pigs showed significant (p < 0.05) decrease in brain nucleotidase and ATPase activities when compared to control or LS alone treated groups. Combined treatment of LS and Mn showed a significant (p < 0.05) decrease in neuronal aryl hydrocarbon hydroxylase (36-40%), ethoxyresorufin-O-deethylase (40-45%), glutathione-S-transferase (27-31%), and quinone reductase (24-25%) activities when compared to control and LS alone treated animals. Lipid peroxidation, a marker for membrane damage, was found to be relatively more enhanced (58-141%) along with significant (p < 0.05) depletion of GSH levels in LS+Mn-treated animals when compared to control, Mn alone, and LS alone treated groups. The neuronal catalase activity of lathyrus plus Mn-treated animals showed a pronounced decrease (37-49%) when compared to control, Mn, and lathyrus alone treated groups. On the contrary, glutathione peroxidase in brain of Mn and lathyrus alone treated animals indicated a respective increase (p < 0.05) of 18% and 20%, while the combined effect of lathyrus plus Mn exhibited an increase of almost 50% when compared to control guinea pigs. Single parenteral administration of Mn (15 mg/kg b.wt) to guinea pigs followed by single oral intubation of beta-N-oxalyl-L-alpha, beta-diamino propionic acid (ODAP, 75 mg/guinea pig) resulted in a significant increase (143%) in neuronal ODAP content. ODAP (50 mg/kg,iv) treatment to mice pretreated with MnCl2 (10 mg/kg b.wt for 3 days or 40 mg/kg b.wt for 1 day), caused an enhancement in blood-brain barrier (BBB) permeability (129-196%), while ODAP and Mn alone showed relatively less enhancement (66-87%). The lumbar region of LS+Mn showed a number of vacuolated areas of variegated size and chromatolytic neurons, along with a few degenerated neurons. These results suggest that Mn may potentiate the neurotoxicity of lathyrus/ODAP by altering the BBB permeability.
Food Toxicology Laboratory, Indian Institute of Toxicology Research, Council of Scientific Research, Mahatma Gandhi Marg, Lucknow, India.
Geeta
G
Mishra
Rakesh
R
Shukla
Mahdi
M
Hasan
Subhash K
SK
Khanna
Mukul
M
Das
D000599:Amino Acids, Diamino / Q000032:analysis / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D006168:Guinea Pigs; D007842:Lathyrism / Q000209:etiology*; D027807:Lathyrus; D008297:Male; D008345:Manganese / Q000494:pharmacology*; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010544:Peroxidases / Q000378:metabolism
D000599:Amino Acids, Diamino; C100126:oxalyldiaminopropionic acid; D008345:Manganese; D010544:Peroxidases