Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: A combined retrograde tracing and immunocytochemical study in the rat
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Abstract
In order to develop a rodent model displaying a progressive degeneration of the dopamine
neurons of the substantia nigra, we bilaterally injected the tracer substance FluoroGold
into the terminal field of the nigrostriatal projection, i.e. the striatum. One week
later, rats received unilateral injections of 20 micrograms 6-hydroxydopamine into
one of the two striatal tracer deposits. Groups of animals were killed one, two, four,
eight and 16 weeks later. Ipsilateral to the lesion there was a progressive loss of
FluoroGold-labelled nigral cells, with cell counts dropping from 96% of the contralateral
side at one week to 59% at two weeks, 35% at four weeks, 23% at eight weeks and down
to 15% at 16 weeks. Labelled nigral neurons ipsilateral to the lesion showed a moderate
to marked atrophy at all investigated time points. The number of tyrosine hydroxylase-immunoreactive
cells was decreased to 83% of contralateral at one week, 39% at two weeks, 44% at
four weeks, 34% at eight weeks and 52% at 16 weeks postlesion. Rhodamine fluorescence
immunocytochemistry showed that the proportion of surviving ipsilateral fluorogold-labelled
cells displaying immunoreactivity for tyrosine hydroxylase was 69% at one week postlesion,
51% at two weeks, 63% at four weeks, 69% at eight weeks and 76% at 16 weeks. We conclude
that injection of 6-hydroxydopamine into the terminal field of nigral dopaminergic
neurons causes a progressive degeneration of these cells, starting between one and
two weeks after lesion and continuing over eight to 16 weeks. This degeneration is
preceded, and accompanied by, cellular atrophy and a partial loss of marker enzyme
expression, thus yielding an animal model which mimics the degenerative processes
in Parkinson's disease more closely than the animal models available so far. The present
model may be helpful in investigating the in vivo effects of putative neuroprotective
agents and neurotrophic factors.