The intrastriatal injection of thrombin in rat induced a retrograde apoptotic degeneration of nigral dopaminergic neurons through synaptic elimination.
We have performed intrastriatal injection of thrombin and searched for distant effects in the cell body region. In striatum, thrombin produced a slight loss of striatal neurons as demonstrated by neural nuclei immunostaining - a non-specific neuronal marker - and the expression of glutamic acid decarboxylase 67 mRNA, a specific marker for striatal GABAergic interneurons, the most abundant phenotype in this brain area. Interestingly, striatal neuropil contained many boutons immunostained for synaptic vesicle protein 2 and synaptophysin which colocalize with tyrosine hydroxylase (TH), suggesting a degenerative process with pre-synaptic accumulation of synaptic vesicles. When we studied the effects on substantia nigra, we found the disappearance of dopaminergic neurons, shown by loss of TH immunoreactivity, loss of expression of TH and dopamine transporter mRNAs, and disappearance of FluoroGold-labelled nigral neurons. The degeneration of substantia nigra dopaminergic neurons was produced through up-regulation of cFos mRNA, apoptosis and accumulation of alpha-synuclein shown by colocalization experiments. Thrombin effects could be mediated by protease-activated receptor 4 activation, as protease-activated receptor 4-activating peptide mimicked thrombin effects. Our results point out the possible relationship between synapse elimination and retrograde degeneration in the nigral dopaminergic system.
Herrera
Antonio J
AJ
Departamento de Bioquímica, Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
de Pablos
Rocío M
RM
Carreño-Müller
Eloisa
E
Villarán
Ruth F
RF
Venero
José L
JL
Tomás-Camardiel
Mayka
M
Cano
Josefina
J
Machado
Alberto
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009498:Neurotoxins / Q000633:toxicity; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018179:Receptors, Thrombin / Q000187:drug effects / Q000378:metabolism; D012183:Retrograde Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D013266:Stilbamidines; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D016708:Synaptophysin / Q000187:drug effects / Q000378:metabolism; D013917:Thrombin / Q000633:toxicity*; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D016760:Proto-Oncogene Proteins c-fos; D018179:Receptors, Thrombin; D013266:Stilbamidines; C489618:Sv2a protein, rat; D016708:Synaptophysin; D014446:Tyrosine 3-Monooxygenase; D013917:Thrombin; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C112908:protease-activated receptor 4; D004298:Dopamine