Exogenous Ketone Therapy Does Not Protect Brain Tissue After Moderate-sized Intracerebral Hemorrhage Despite Signs of Early Neurological Benefit

Ketone bodies, or ketones, are an alternative energy source and have several nonmetabolic signaling actions, such as inhibiting inflammation. Because of this, exogenous ketone supplementation has been used to help treat various diseases. β-hydroxybutyrate (βHB) is the major ketone body that has reduced neurological injury and brain edema in animal models of ischemic stroke and traumatic brain injury. However, the therapeutic potential of βHB in intracerebral hemorrhage (ICH) has not yet been determined. Here we investigated the effects of exogenous βHB treatment following ICH on inflammation, edema, injury size, and functional outcomes. To do this, we administered 250 mg/kg of βHB (subcutaneously every 12 hours) starting 2 hours after collagenase-induced ICH in rats over 3 experiments. First, we observed that βHB-treated rats had significant reductions in transcript expression of pro-inflammatory markers Il1b (p = 0.0210), Tnfa (p = 0.0108), and Mcp1 (p = 0.0473) 3 days post-ICH. Second, βHB significantly improved neurological deficits measured by the neurological deficit scale on day 3 (p = 0.0416) in another cohort of rats, despite no treatment effect on edema (p = 0.2110). To test whether the effects of acute βHB treatment (for 7 days post-ICH) were chronically sustained, the third experiment used serial behavioural testing which confirmed that βHB significantly improved neurological deficit scores (p = 0.0459) 3 days post-ICH. These effects were not sustained at 7, 14, and 28 days post-ICH (all p≥0.1546). Similarly, βHB treatment did not yield differences in forelimb use asymmetry (all p>0.45) or brain lesion volume (p = 0.3381), the primary endpoint of this study. Thus, our studies show that an acute βHB treatment post-ICH can provide some early signs of functional benefit without evidence of lasting effects or neuroprotection. However, it remains to be tested whether other βHB dosing regimens may favorably affect these and other neurological, behavioral, and biochemical parameters, particularly given the early signals of reduced striatal inflammation.