Post-stroke infections exacerbate ischemic brain injury in middle-aged rats: Immunomodulation and neuroprotection by progesterone

Abstract

We investigated the effect of delayed, prolonged systemic inflammation on stroke outcomes and progesterone (P4) neuroprotection in middle-aged rats. After transient middle cerebral artery occlusion/reperfusion (MCAO) surgery, rats received P4 (8 or 16 mg/kg) or vehicle injections at 2h, 6h and every 24h until day 7 post-occlusion. At 24h post-injury systemic inflammation was induced by giving 3 doses of lipopolysaccharide (LPS; 50 mg/kg, at 4h intervals) to model post-stroke infections. We measured serum brain-derived neurotrophic factor (BDNF), pro-inflammatory cytokines, and behavioral parameters at multiple times. Serum BDNF levels decreased more in the vehicle+LPS group compared to vehicle-alone at 3 and 7 days post-injury (P<0.05). Vehicle-alone showed a significant increase in IL-1β, IL-6, and TNFα levels at different times following stroke and these levels were further elevated in the vehicle+LPS group. P4 at both doses produced a significant (P<0.05) decline in cytokine levels compared to vehicle and vehicle+LPS. P4 restored BDNF levels at 3 and 7 days post-stroke (P<0.05). Behavioral assessment (rotarod, grip strength, sensory neglect and locomotor activity tests) at 3, 5 and 7 days post-stroke revealed that the vehicle group had significant (P<0.05) deficits in all tests compared to intact controls, and performance was worse in the vehicle+LPS group. P4 at both doses produced significant functional improvement on all tests. Systemic inflammation did not show an additive effect on infarct volume but P4 at both doses showed significant infarct reduction. We suggest that post-stroke infection exacerbates stroke outcomes and P4 exerts neuroprotective/modulatory effects through its systemic anti-inflammatory and BDNF regulatory actions.

Progesterone in transient ischemic stroke: a dose–response study

“…PROG treatment at 8, 16, and 32 mg/kg led to behavioral restoration and decreased infarct volumes. Additional support for the results reported here is provided by the neuroprotective effectiveness of PROG treatment demonstrated in different models of stroke (Ishrat et al 2009, 2012; Yousuf et al 2013; Atif et al 2013; Gibson and Murphy 2004; Gibson et al 2011). …”

“…PROG effects are currently being studied under two independent phase III clinical trials for TBI (Protect III, at http://www.clinicaltrials.gov/NCT00822900; SyNAPSe, at http://www.synapse-trial.com). Increasing pre-clinical evidence from our and other laboratories around the world provides important corroboration that PROG treatment improves functional recovery and reduces brain infarction in different stroke models (Atif et al 2013; Yousuf et al 2013; De Nicola et al 2013; Gibson et al 2011; Wong et al 2013). …”

Aging aggravates ischemic stroke-induced brain damage in mice with chronic peripheral infection

“…Indeed, the amount of infiltrating T cells have been shown to dramatically increase at 5 day postinjury in the same pMCAO model, as used in the current study (Zhou et al, 2013). TNF-a on the other hand is a well-characterized proinflammatory cytokine contributing to the ischemic damage (Hallenbeck, 2002), and TNF-a levels in plasma have been shown to be increased not only in preclinical stroke models but also in ischemic patients (Sotgiu et al, 2006;Yousuf et al, 2013). The observed increase in the levels of plasma IL-17A and TNF-a in the current study thus have clinical relevance.…”

Poststroke Inflammasome Expression and Regulation in the Peri-Infarct Area by Gonadal Steroids after Transient Focal Ischemia in the Rat Brain

“…The past years have provided evidence that E2 and P are neuroprotective in experimentally induced ischemic stroke [14,16,18,19,23] and hamper or even prevent neuroinflammatory responses in the injured CNS [14,50,51,52,53,54]. It is generally assumed and documented that astroglia and microglia function is positively correlated with beneficial steroid effects, and that such hormone-glia interactions ameliorate hypoxia-related brain damage [55,56,57,58,59,60].…”