title: Atorvastatin reduces functional deficits caused by photodynamic therapy in rats.
abstract: Clinical studies have indicated that photodynamic therapy (PDT) significantly prolonged the median survival of patients with gliomas. Experimental studies demonstrate that increasing optical energy and photosensitizer dose leads to increased volume of tumor necrosis. However, increasing the light dose delivered to the tumor may increase the risks of inducing permanent neurological deficits. In the current study, we sought to test the behavioral deficits induced in normal rats by brain PDT and the neurorestorative effects of atorvastatin on PDT-induced behavioral deficits. Considering its potential as a combination treatment of brain tumors, we investigated both in vitro and in vivo whether atorvastatin treatment promotes brain tumor growth. Non-tumored Fischer rats received PDT (n=18). Nine of the PDT-treated animals were treated with atorvastatin. Control animals underwent the same surgical procedure, but did not receive Photofrin and laser light. PDT-treated animals had significant behavioral deficits on days 2, 5, 7, 9 and 14 after PDT, compared with surgery controls. PDT-treated animals receiving atorvastatin displayed significantly ameliorated behavioral deficits on days 7, 9 and 14 after PDT, compared to PDT-treated rats. In vitro tumor cell viability and growth were evaluated. Atorvastatin did not affect the growth of glioma cells. Fischer rats with intracranial 7-day-old 9L glioma tumor cell implantation were randomly subjected to no treatment, PDT alone, atorvastatin alone, or combined treatment with atorvastatin and PDT (6 rats/group). Our data indicate that atorvastatin did not promote tumor growth in either PDT treated and non-treated rats. However, atorvastatin significantly reduced the cell damage caused by PDT. To further test the mechanisms underlying the atorvastatin-mediated reduction of functional deficits, we investigated the effects of atorvastatin on angiogenesis and synaptogenesis. Our data demonstrate that atorvastatin significantly induced angiogenesis and synaptogenesis in the PDT-damaged brain tissue. Our data indicate that PDT induces functional deficits. Atorvastatin treatment promotes functional restoration after PDT, but does not promote glioma growth in vitro and in vivo. Atorvastatin reduces astrocyte and endothelial cell damage caused by PDT and induces angiogenesis and synaptogenesis after PDT. Thus consideration and further testing of the combination of atorvastatin and PDT for the treatment of glioma is warranted.
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Zheng
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.forename: Yong
authors.initials: Y
authors.lastname: Lu
authors.forename: James
authors.initials: J
authors.lastname: Jiang
authors.forename: Danping
authors.initials: D
authors.lastname: Zhao
authors.forename: Christopher
authors.initials: C
authors.lastname: Ding
authors.forename: Hongyan
authors.initials: H
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D000069059:Atorvastatin; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017323:Dihematoporphyrin Ether / Q000633:toxicity; D042783:Endothelial Cells / Q000187:drug effects; D005910:Glioma / Q000473:pathology / Q000628:therapy; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D001523:Mental Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010778:Photochemotherapy / Q000009:adverse effects*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D016708:Synaptophysin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D018696:Neuroprotective Agents; D011758:Pyrroles; D016708:Synaptophysin; D042461:Vascular Endothelial Growth Factor A; D014841:von Willebrand Factor; D017323:Dihematoporphyrin Ether; D000069059:Atorvastatin