Bexarotene targets autophagy and is protective against thromboembolic stroke in aged mice with tauopathy.
Stroke is a highly debilitating, often fatal disorder for which current therapies are suitable for only a minor fraction of patients. Discovery of novel, effective therapies is hampered by the fact that advanced age, primary age-related tauopathy or comorbidities typical to several types of dementing diseases are usually not taken into account in preclinical studies, which predominantly use young, healthy rodents. Here we investigated for the first time the neuroprotective potential of bexarotene, an FDA-approved agent, in a co-morbidity model of stroke that combines high age and tauopathy with thromboembolic cerebral ischemia. Following thromboembolic stroke bexarotene enhanced autophagy in the ischemic brain concomitantly with a reduction in lesion volume and amelioration of behavioral deficits in aged transgenic mice expressing the human P301L-Tau mutation. In in vitro studies bexarotene increased the expression of autophagy markers and reduced autophagic flux in neuronal cells expressing P301L-Tau. Bexarotene also restored mitochondrial respiration deficits in P301L-Tau neurons. These newly described actions of bexarotene add to the growing amount of compelling data showing that bexarotene is a potent neuroprotective agent, and identify a novel autophagy-modulating effect of bexarotene.
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Mikko T
MT
Huuskonen
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Sanna
S
Loppi
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Hiramani
H
Dhungana
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Velta
V
Keksa-Goldsteine
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Sighild
S
Lemarchant
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Paula
P
Korhonen
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Sara
S
Wojciechowski
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Eveliina
E
Pollari
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Piia
P
Valonen
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Juho
J
Koponen
Department of Life Science, Gakushuin University, Toshiba-ku, Tokyo, Japan.
Akihiko
A
Takashima
Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Gary
G
Landreth
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Gundars
G
Goldsteins
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Tarja
T
Malm
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Jari
J
Koistinaho
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Katja M
KM
Kanninen
D000375:Aging; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000077610:Bexarotene; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D024801:Tauopathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013923:Thromboembolism / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D018696:Neuroprotective Agents; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene