From Drugs of Abuse to Parkinsonism: The MPTP Mouse Model of Parkinson’s Disease - Drugs of Abuse: Neurological Reviews and Protocols - page 106

readily absorbed and crosses the blood-brain barrier. The toxin is converted
to an active toxic metabolite, 1-methyl-4-phenylpyridinium (MPP + ), by the
monoamine oxidase type B enzyme located in the astroglial cells (54) . The
produced MPP + is taken up into the nigrostriatal DA nerve terminals selectively
by the DA uptake transporter (DAT) (55) . The elevated cytoplasmic MPP +
level may in turn cause the release and accumulation of the excitatory amino
acid transmitter glutamate and Ca 2+ within the affl icted neurons, resulting
in an inhibition of complex I of the mitochondrial electron transport chain
system and a production of free radicals (56 , 57) . Impairment of respiration
and oxidative damage of the mitochondria may lead to the depletion of cellular
ATP and eventual neuronal death (58) . Subacute MPTP injections and MPP +
production may induce apoptosis in dopaminergic neurons (59) and that could
serve to initiate neuronal degeneration. On the other hand, subacute MPTP
treatment causes endogenous reactive gliogenesis from striatal progenitor
cells in response to neuronal injury (60 , 61) . Nevertheless, these mechanistic
pathways are established under acute or subacute conditions; whether they
are associated with the slow, progressive development of neurodegeneration
in PD is not understood.
Subacute MPTP treatment in mice produces only a transient neurotoxic
insult, which reverses spontaneously and has no long-term neurodegenerative
consequences, and thus may not be relevant to the progressive nature of human
PD. Therefore, it would be extremely valuable to develop a long-term animal
model that closely mimics the phenotypes and neuropathology exhibited by
PD patients. Availability of such an animal model would allow further testing
of mechanisms underlying the disease process and might lead to the discovery
of novel, neuroprotective measures for slowing or arresting the progressive
deterioration of motor performance in PD patients.
4.2. The Chronic Mouse MPTP/Probenecid Model
Pharmacokinetic consideration could be one of the underlying reasons why
acute and subacute MPTP injections do not produce a sustained neurological
insult in laboratory animals. It has been established that MPTP in rodents,
following its peripheral administration, is rapidly excreted through the kidney
(62) . After reaching the central nervous system (CNS), this toxin and its active
metabolite, MPP + , are quickly cleared from the brain (63) . Hence, investigators
tend to intensify MPTP neurotoxicity by giving high doses and/or shortening
the time period between successive toxin injections ( see the preceding discus-
sion on acute and subacute models). Other approaches have also been adopted
to enhance MPTP neurotoxicity in mice by using agents that inhibit the
central clearance of MPP + and/or the renal excretion of MPTP. When MPTP
is coadministered with diethyldithiocarbamate (64 , 65) or acetaldehyde (66) ,