title: HIV protease inhibitors provide neuroprotection through inhibition of mitochondrial apoptosis in mice.
abstract: Neuroprotection can be achieved by preventing apoptotic death of postmitotic cells. Apoptotic death can occur by either a caspase-dependent mechanism, involving cytochrome c, apoptosis protease-activating factor-1 (Apaf-1), and caspase-9, or a caspase-independent mechanism, involving apoptosis-inducing factor (AIF). HIV protease inhibitors (PIs) avert apoptosis in part by preventing mitochondrial outer membrane permeabilization (MOMP), but the precise mechanism by which they work is not known. Here, we evaluated the impact of the PIs in a mouse model of retinal detachment (RD) in vivo and in murine primary retinal cell cultures in vitro. Oral administration of the PIs nelfinavir and ritonavir significantly inhibited photoreceptor apoptosis, while preventing the translocation of AIF from mitochondria to the nucleus as well as the activation of caspase-9. RD-induced photoreceptor apoptosis was similarly inhibited in mice carrying hypomorphic mutations of the genes encoding AIF or Apaf-1. Nelfinavir attenuated apoptosis as well as mitochondrial release of AIF and cytochrome c, and subsequent activation of caspase-9 in vitro, in photoreceptor cultures exposed to starvation or monocyte chemoattractant protein-1-stimulated (MCP-1-stimulated) macrophages. Our results suggest that the MOMP inhibition by PIs involved interruption of both caspase-dependent and caspase-independent apoptosis pathways and that PIs may be clinically useful for the treatment of diseases caused by excessive apoptosis.
authors.affiliation: Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Toshio
authors.initials: T
authors.lastname: Hisatomi
authors.forename: Toru
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Kousuke
authors.initials: K
authors.lastname: Noda
authors.forename: Lama
authors.initials: L
authors.lastname: Almulki
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Miyahara
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nakao
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ito
authors.forename: Haicheng
authors.initials: H
authors.lastname: She
authors.forename: Riichiro
authors.initials: R
authors.lastname: Kohno
authors.forename: Norman
authors.initials: N
authors.lastname: Michaud
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishibashi
authors.forename: Ali
authors.initials: A
authors.lastname: Hafezi-Moghadam
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Badley
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
mesh_terms: D000818:Animals; D017209:Apoptosis; D053453:Caspase 9 / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D019888:Nelfinavir / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D012160:Retina / Q000166:cytology
chemical_list: D018932:Chemokine CCL2; D017320:HIV Protease Inhibitors; D018696:Neuroprotective Agents; D045304:Cytochromes c; D053453:Caspase 9; D019888:Nelfinavir