Hb. Jones et al., ULTRASTRUCTURAL PATHOLOGY AND CYTOCHEMICAL INVESTIGATIONS OF L-2-CHLOROPROPIONIC ACID-INDUCED NEUROINTOXICATION OF THE RAT CEREBELLUM, Acta Neuropathologica, 93(3), 1997, pp. 241-251
The objectives of the studies described were to assess the ultrastruct
ural neuropathology, blood-brain barrier (BBB) integrity and calcium s
tatus of the cerebellum of rats following a single dose of 750 mg . kg
(-1) L-2-chloropropionic acid (L-2-CPA). The first indications of into
xication appeared at 36 h when condensation of many granule cells asso
ciated with Purkinje cell degeneration and marked astroglial swelling
were observed. Some electronlucent granule cells were also noted lying
amongst these condensed forms. Condensed granule cells had swollen, e
lectron-lucent mitochondria, dilated Golgi apparatus and nuclear crena
tion. Occasionally, areas of granule cell necrosis were also present a
t this time. Granule cell condensation probably represents a prelimina
ry and irreversible stage in an excitotoxic process that leads to necr
osis At 48 and 72 h, most granule cells were necrotic, and occasionall
y, extravasation of both erythrocytes and leucocytes into the expanded
extravascular space was observed. Evaluation of the BBB by ultrastruc
tural cytochemical visualisation of horseradish peroxidase injected i.
v. 2 min before killing by perfusion fixation showed substantial leaka
ge. At 36 h post-dose, ultrastructural calcium localisation using oxal
ate/pyroantimonate precipitation demonstrated a substantial increase i
n calcium pyroantimonate precipitate in mitochondria and other membran
ous cytoplasmic organelles (especially the Golgi apparatus) in condens
ed granule cells, but with little in their nuclei. However, their imme
diate neighbours (of ostensibly normal ultrastructural appearances) co
ntained greater amounts of intranuclear precipitate. Swollen astroglia
l cells (especially the Bergmann glia) contained considerable quantiti
es of precipitate. A possible excitotoxic mechanism via L-2-CPA-induce
d NMDA receptor agonism leading to overwhelming calcium influx and dis
ruption of cellular calcium homeostasis is proposed.