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
neurotrophic factor expression in the ischemic hippocampus. Treatment with
progesterone significantly attenuated stress-induced microglia priming by modulating polarized microglia and the inflammatory environment in the hippocampus, the area most vulnerable to ischemic injury. Our findings can be taken to suggest that
progesterone holds potential as a candidate for clinical testing in
ischemic stroke where high stress may be a contributing factor.