Ultrastructural alterations induced by 1-methyl-4-phenylpyridinium (MPP+) in canine substantia nigra and rat mesencephalon in vitro.
Explants of canine substantia nigra (SN) and rat mesencephalon (MES), grown in organotypic culture, were incubated with 1-methyl-4-phenylpyridinium (MPP+) and examined for ultrastructural changes. Prolonged exposure (3 days) to doses ranging from 0.1 nM to 10 microM MPP+ resulted in total destruction of all constituents (neuronal and glial) of canine SN cultures. No association was noted between MPP+-induced toxicity and age of canine SN cultures. The first ultrastructural change observed in canine SN cultures incubated with 0.1 nM MPP+ was at 3 h. Grossly swollen mitochondria were noted in large nerve cells. Swollen mitochondria were present in all cells of canine SN cultures by 8 h of incubation with MPP+. Only those rat MES cultures with relatively high preincubation levels of homovanillac acid, determined as an index of viable dopaminergic neurons, incubated with MPP+ (10 microM) for up to 8 days exhibited ultrastructural changes, namely, a swelling of mitochondria within the cytoplasm of large nerve cells. These findings suggest that continual exposure to MPP+ in vitro results in a generalized, nonspecific toxicity in those species known to be susceptible to the parent compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in vivo. However, the initial ultrastructural change, i.e., a swelling of mitochondria, may be the same in all species regardless of sensitivity suggesting that the ultimate mechanism underlying MPP+-toxicity relates to mitochondrial function.
Christie-Pope
B C
BC
Division of Neuropathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2561.
Burns
R S
RS
Whetsell
W O
WO
D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D003470:Culture Media; D004285:Dogs / Q000033:anatomy & histology / Q000502:physiology*; D006719:Homovanillic Acid / Q000378:metabolism; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009498:Neurotoxins / Q000494:pharmacology; D009924:Organ Culture Techniques; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats / Q000033:anatomy & histology / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
D003470:Culture Media; D009498:Neurotoxins; D011726:Pyridinium Compounds; D015655:1-Methyl-4-phenylpyridinium; D006719:Homovanillic Acid