HIV protease inhibitors provide neuroprotection through inhibition of mitochondrial apoptosis in mice.
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.
Hisatomi
Toshio
T
Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, USA.
Nakazawa
Toru
T
Noda
Kousuke
K
Almulki
Lama
L
Miyahara
Shinsuke
S
Nakao
Shintaro
S
Ito
Yasuhiro
Y
She
Haicheng
H
Kohno
Riichiro
R
Michaud
Norman
N
Ishibashi
Tatsuro
T
Hafezi-Moghadam
Ali
A
Badley
Andrew D
AD
Kroemer
Guido
G
Miller
Joan W
JW
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
D018932:Chemokine CCL2; D017320:HIV Protease Inhibitors; D018696:Neuroprotective Agents; D045304:Cytochromes c; D053453:Caspase 9; D019888:Nelfinavir