Drugs targeting intermediate filaments can improve neurosupportive properties of astrocytes.
In response to central nervous system (CNS) injury, astrocytes upregulate intermediate filament (nanofilament) proteins GFAP and vimentin. Whereas the intermediate filament upregulation in astrocytes is important for neuroprotection in the acute phase of injury, in some contexts it might inhibit some of the regenerative processes later on. Thus, timely modulation of the astrocyte intermediate filaments was proposed as a strategy to promote brain repair. We used clomipramine, epoxomicin and withaferin A, drugs reported to decrease the expression of GFAP, and assessed their effect on neurosupportive properties and resilience of astrocytes to oxygen and glucose deprivation (OGD). Clomipramine decreased protein levels of GFAP, as well as vimentin and nestin, and did not affect astrocyte resilience to oxidative stress. Withaferin A sensitized astrocytes to OGD. Both clomipramine and epoxomicin promoted the attachment and survival of neurons co-cultured with astrocytes under standard culture conditions. Moreover, epoxomicin increased neurosupportive properties of astrocytes after OGD. Our data point to clomipramine and epoxomicin as potential candidates for astrocyte modulation to improve outcome after CNS injury.
Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. Electronic address: yolanda.depablo@neuro.gu.se.
Yolanda
Y
de Pablo
Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Meng
M
Chen
Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Elin
E
Möllerström
Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia; University of Newcastle, New South Wales, Australia.
Marcela
M
Pekna
Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia; University of Newcastle, New South Wales, Australia. Electronic address: milos.pekny@neuro.gu.se.
Milos
M
Pekny
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002997:Clomipramine / Q000494:pharmacology* / Q000633:toxicity; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D007382:Intermediate Filaments / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000633:toxicity; D009842:Oligopeptides / Q000494:pharmacology / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D054358:Withanolides / Q000494:pharmacology* / Q000633:toxicity
D018696:Neuroprotective Agents; D009842:Oligopeptides; D017382:Reactive Oxygen Species; D054358:Withanolides; D005947:Glucose; C009684:withaferin A; D002997:Clomipramine; C078846:epoxomicin
Astrocytes; Clomipramine; Epoxomicin; Intermediate filaments (nanofilaments); Neuroprotection; Oxidative stress; Oxygen and glucose deprivation