Abstract DP077: Neuroprotective Potential of Remote Hepatic Cooling in Ischemic Stroke via Modulation of Liver-derived FGF21

Background: Acute ischemic stroke (AIS) induces systemic responses that extend beyond the brain, including profound hepatic metabolic and inflammatory alterations that can exacerbate cerebral injury. While hypothermia protects the brain in stroke, current methods are complex or cause systemic side effects. This study investigated hepatic cooling (HC), a novel non-invasive approach to attenuate stroke-induce liver-brain crosstalk, focusing on fibroblast growth factor 21 (FGF21) as a key mediator. Methods: Male Sprague-Dawley rats (n=140) underwent 2-h middle cerebral artery occlusion (MCAO) followed by reperfusion. HC (liver temperature reduced to ~34°C) was initiated 30 min before reperfusion. In a subset, cerebral tumor necrosis factor-α (TNF-α) was knocked down by intracerebral adenovirus-associated virus injection 2 weeks prior. Infarct volume, neurological deficits and long-term sensorimotor/cognitive outcomes (adhesive tape, grid walk, rota-rod, beam balance, and the Morris water maze) were assessed. mRNA and protein levels of TNF-α and FGF21 in brain, serum, liver, and hepatic cAMP response element-binding protein H (CREBH) in liver, were measured using rt-PCR, Western blot, and ELISA. Haptic oxidative stress was evaluated by SOD and MDA via ELISA. Results: HC selectively reduced liver temperature without altering brain or core body temperature, significantly decreasing infarct volume and improving both short- and long-term neurological outcomes. Stroke induced hepatic oxidative stress (↑MDA, ↓SOD), elevated TNF-α in brain, serum, and liver (protein only in liver), along with hepatic CREBH and FGF21, and cerebral FGF21, which were all reversed by cerebral TNF-α knockdown. Temporal analysis showed FGF21 rose first in liver, then serum, then brain, which were attenuated at all sites by HC. HC suppressed hepatic oxidative stress, reduced hepatic CREBH/FGF21 and neuronal FGF21 expression, and limited brain injury. In non-stroke rats, HC lowered hepatic CREBH/FGF21 and circulating/brain FGF21 protein without affecting TNF-α. Conclusion: Ischemia-initiated TNF-α from the brain triggers hepatic oxidative stress and drives hepatic CREBH–FGF21 activation, with liver-derived FGF21 subsequently entering the brain and aggravating injury. HC interrupts this cascade, highlighting remote organ cooling as a viable neuroprotective strategy. These findings open a translational avenue for targeting peripheral organ–CNS interactions to improve AIS outcomes.