Potentiation of neurotoxicity ofLathyrus sativusby manganese: Alterations in blood–brain barrier permeability

Abstract

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.

Manganese Is Essential for Neuronal Health

“…Even less is known about Mn efflux across the blood-CSF barrier; however, evidence points to diffusion as the major mechanism of Mn efflux (306). Recent studies suggest that Mn may alter the permeability of the BBB, contributing to its own toxic effect and that of other cytotoxins (78, 188).…”