HIV protease inhibitors provide neuroprotection through inhibition of mitochondrial apoptosis in mice

Toshio Hisatomi, Toru Nakazawa, Kousuke Noda, Lama Almulki, Shinsuke Miyahara, Shintaro Nakao, Yasuhiro Ito, Haicheng She, Riichiro Kohno, Norman Michaud, Tatsuro Ishibashi, Ali Hafezi-Moghadam, Andrew David Badley, Guido Kroemer, Joan W. Miller

Research output: Contribution to journalArticle

52 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2025-2038
Number of pages14
JournalJournal of Clinical Investigation
Volume118
Issue number6
DOIs
StatePublished - Jun 2 2008

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HIV Protease Inhibitors
Apoptosis Inducing Factor
Apoptosis
Caspases
Protease Inhibitors
Caspase 9
Nelfinavir
Mitochondrial Membranes
Retinal Detachment
Cytochromes c
Peptide Hydrolases
Ritonavir
Primary Cell Culture
Neuroprotection
Chemokine CCL2
Starvation
Oral Administration
Mitochondria
Cell Death
Macrophages

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hisatomi, T., Nakazawa, T., Noda, K., Almulki, L., Miyahara, S., Nakao, S., ... Miller, J. W. (2008). HIV protease inhibitors provide neuroprotection through inhibition of mitochondrial apoptosis in mice. Journal of Clinical Investigation, 118(6), 2025-2038. https://doi.org/10.1172/JCI34267

HIV protease inhibitors provide neuroprotection through inhibition of mitochondrial apoptosis in mice. / Hisatomi, Toshio; Nakazawa, Toru; Noda, Kousuke; Almulki, Lama; Miyahara, Shinsuke; Nakao, Shintaro; Ito, Yasuhiro; She, Haicheng; Kohno, Riichiro; Michaud, Norman; Ishibashi, Tatsuro; Hafezi-Moghadam, Ali; Badley, Andrew David; Kroemer, Guido; Miller, Joan W.

In: Journal of Clinical Investigation, Vol. 118, No. 6, 02.06.2008, p. 2025-2038.

Research output: Contribution to journalArticle

Hisatomi, T, Nakazawa, T, Noda, K, Almulki, L, Miyahara, S, Nakao, S, Ito, Y, She, H, Kohno, R, Michaud, N, Ishibashi, T, Hafezi-Moghadam, A, Badley, AD, Kroemer, G & Miller, JW 2008, 'HIV protease inhibitors provide neuroprotection through inhibition of mitochondrial apoptosis in mice', Journal of Clinical Investigation, vol. 118, no. 6, pp. 2025-2038. https://doi.org/10.1172/JCI34267
Hisatomi, Toshio ; Nakazawa, Toru ; Noda, Kousuke ; Almulki, Lama ; Miyahara, Shinsuke ; Nakao, Shintaro ; Ito, Yasuhiro ; She, Haicheng ; Kohno, Riichiro ; Michaud, Norman ; Ishibashi, Tatsuro ; Hafezi-Moghadam, Ali ; Badley, Andrew David ; Kroemer, Guido ; Miller, Joan W. / HIV protease inhibitors provide neuroprotection through inhibition of mitochondrial apoptosis in mice. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 6. pp. 2025-2038.
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AU - Nakao, Shintaro

AU - Ito, Yasuhiro

AU - She, Haicheng

AU - Kohno, Riichiro

AU - Michaud, Norman

AU - Ishibashi, Tatsuro

AU - Hafezi-Moghadam, Ali

AU - Badley, Andrew David

AU - Kroemer, Guido

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