Stress primes microglial polarization after global ischemia: Therapeutic potential of progesterone

• Published in: Brain, behavior, and immunity behavior, and immunity, 2017-11, Vol.66, p.177-192
• Main Authors: Espinosa-Garcia, Claudia, Sayeed, Iqbal, Yousuf, Seema, Atif, Fahim, Sergeeva, Elena G., Neigh, Gretchen N., Stein, Donald G.
• Format: Article
• Language: English
• Subjects: Animals; Brain Ischemia - complications; Brain Ischemia - metabolism; Brain Ischemia - pathology; Cell Polarity; Depression - complications; Encephalitis - complications; Encephalitis - drug therapy; Encephalitis - metabolism; Global ischemia; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Inflammation; Inflammation Mediators - metabolism; M1/M2 polarization; Male; Microglia; Microglia - drug effects; Microglia - metabolism; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Neuroprotective Agents - administration & dosage; Progesterone; Progesterone - administration & dosage; Rats, Sprague-Dawley; Stress; Stress, Psychological - complications; Stress, Psychological - metabolism; Stress, Psychological - pathology
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2017.06.012

[Display omitted] •Stress primes microglia, worsening inflammatory response to global ischemic injury.•Stress exacerbates neuron loss and microglia activation in the hippocampal CA1 region.•Stress induces phenotypic and functional changes in M1/M2 polarized microglia.•Progesterone ameliorates stress-induced microglial changes and improves outcome. Despite the fact that stress is associated with increased risk of stroke and worsened outcome, most preclinical studies have ignored this comorbid factor, especially in the context of testing neuroprotective treatments. Preclinical research suggests that stress primes microglia, resulting in an enhanced reactivity to a subsequent insult and potentially increasing vulnerability to stroke. Ischemia-induced activated microglia can be polarized into a harmful phenotype, M1, which produces pro-inflammatory cytokines, or a protective phenotype, M2, which releases anti-inflammatory cytokines and neurotrophic factors. Selective modulation of microglial polarization by inhibiting M1 or stimulating M2 may be a potential therapeutic strategy for treating cerebral ischemia. Our laboratory and others have shown progesterone to be neuroprotective against ischemic stroke in rodents, but it is not known whether it will be as effective under a comorbid condition of chronic stress. Here we evaluated the neuroprotective effect of progesterone on the inflammatory response in the hippocampus after exposure to stress followed by global ischemia. We focused on the effects of microglial M1/M2 polarization and pro- and anti-inflammatory mediators in stressed ischemic animals. Male Sprague-Dawley rats were exposed to 8 consecutive days of social defeat stress and then subjected to global ischemia or sham surgery. The rats received intraperitoneal injections of progesterone (8mg/kg) or vehicle at 2h post-ischemia followed by subcutaneous injections at 6h and once every 24h post-injury for 7days. The animals were killed at 7 and 14days post-ischemia, and brains were removed and processed to assess outcome measures using histological, immunohistochemical and molecular biology techniques. Pre-ischemic stress (1) exacerbated neuronal loss and neurodegeneration as well as microglial activation in the selectively vulnerable CA1 hippocampal region, (2) dysregulated microglial polarization, leading to upregulation of both M1 and M2 phenotype markers, (3) increased pro-inflammatory cytokine expression, and (4) reduced anti-inflammatory cytokine and