PMID- 19442825 OWN - NLM STAT- MEDLINE DCOM- 20090804 LR - 20131121 IS - 1872-9711 (Electronic) IS - 0161-813X (Linking) VI - 30 IP - 3 DP - 2009 May TI - The intranigral injection of tissue plasminogen activator induced blood-brain barrier disruption, inflammatory process and degeneration of the dopaminergic system of the rat. PG - 403-13 LID - 10.1016/j.neuro.2009.02.011 [doi] AB - Tissue-type plasminogen activator (tPA) is the only drug approved for the treatment of thromboembolic stroke, but it might lead to some neurotoxic side effects. tPA is a highly specific serine proteinase, one of the two principal plasminogen activators and one of the three trypsin-like serine proteinases of the tissue kallikrein family. We have observed that tPA injection in the SN leads to the degeneration of the dopaminergic neurons in a dose-dependent manner, without affecting the GABAergic neurons. We also found that tPA injected in the substantia nigra of rats produced the disruption of the blood-brain barrier (BBB) integrity, the induction of microglial activation, the loss of astroglia and the expression of aquaporin 4 (AQP4), as well as an increase in the expression of NMDA receptors and the brain derived neurothrophic factor (BDNF). All these effects, along with the changes produced in the phosphorylated forms of several MAP kinases and the transcription factor CREB, and the increase in the expression of nNOS and iNOS observed under our experimental conditions, could be involved in the loss of dopaminergic neurons. FAU - Villaran, Ruth F AU - Villaran RF AD - Departamento de Bioquimica, Bromatologia, Toxicologia y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, c/Profesor Garcia Gonzalez, 2, 41012 Sevilla, Spain. FAU - de Pablos, Rocio M AU - de Pablos RM FAU - Arguelles, Sandro AU - Arguelles S FAU - Espinosa-Oliva, Ana M AU - Espinosa-Oliva AM FAU - Tomas-Camardiel, Mayka AU - Tomas-Camardiel M FAU - Herrera, Antonio J AU - Herrera AJ FAU - Cano, Josefina AU - Cano J FAU - Machado, Alberto AU - Machado A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20090225 PL - Netherlands TA - Neurotoxicology JT - Neurotoxicology JID - 7905589 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Inflammation Mediators) RN - 0 (alpha-Synuclein) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type I) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 3.4.21.68 (Tissue Plasminogen Activator) RN - VTD58H1Z2X (Dopamine) SB - IM MH - Animals MH - Astrocytes/drug effects MH - Blood-Brain Barrier/*drug effects MH - Brain-Derived Neurotrophic Factor/metabolism MH - Dopamine/*metabolism MH - Inflammation Mediators/*metabolism MH - MAP Kinase Signaling System/drug effects MH - Male MH - Microglia/drug effects MH - Microinjections MH - Neurons/cytology/drug effects/metabolism MH - Nitric Oxide Synthase Type I/metabolism MH - Nitric Oxide Synthase Type II/metabolism MH - Rats MH - Rats, Wistar MH - Substantia Nigra/cytology/*drug effects/metabolism MH - Tissue Plasminogen Activator/*toxicity MH - alpha-Synuclein/metabolism MH - gamma-Aminobutyric Acid EDAT- 2009/05/16 09:00 MHDA- 2009/08/06 09:00 CRDT- 2009/05/16 09:00 PHST- 2008/10/24 00:00 [received] PHST- 2009/02/05 00:00 [revised] PHST- 2009/02/17 00:00 [accepted] PHST- 2009/05/16 09:00 [entrez] PHST- 2009/05/16 09:00 [pubmed] PHST- 2009/08/06 09:00 [medline] AID - S0161-813X(09)00049-7 [pii] AID - 10.1016/j.neuro.2009.02.011 [doi] PST - ppublish SO - Neurotoxicology. 2009 May;30(3):403-13. doi: 10.1016/j.neuro.2009.02.011. Epub 2009 Feb 25.