Sander Noam H, Soni Shubham, Wilkinson Cassandra M, Khiabani Elmira, Dyck Jason R B, Colbourne Frederick
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada.
PLoS One. 2024 Dec 5;19(12):e0311778. doi: 10.1371/journal.pone.0311778. eCollection 2024.
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.
酮体，或称为酮，是一种替代能源，具有多种非代谢信号传导作用，如抑制炎症。因此，外源性补充酮体已被用于帮助治疗各种疾病。β-羟基丁酸（βHB）是主要的酮体，在缺血性中风和创伤性脑损伤的动物模型中，它能减轻神经损伤和脑水肿。然而，βHB在脑出血（ICH）中的治疗潜力尚未确定。在此，我们研究了脑出血后外源性βHB治疗对炎症、水肿、损伤大小和功能结局的影响。为此，我们在大鼠胶原酶诱导脑出血后2小时开始，在3个实验中每12小时皮下注射250mg/kg的βHB。首先，我们观察到βHB治疗的大鼠在脑出血后3天促炎标志物Il1b（p = 0.0210）、Tnfa（p = 0.0108）和Mcp1（p = 0.0473）的转录表达显著降低。其次，在另一组大鼠中，βHB在第3天显著改善了通过神经功能缺损量表测量的神经功能缺损（p = 0.0416），尽管对水肿没有治疗效果（p = 0.2110）。为了测试急性βHB治疗（脑出血后7天）的效果是否能长期持续，第三个实验采用了系列行为测试，证实βHB在脑出血后3天显著改善了神经功能缺损评分（p = 0.0459）。这些效果在脑出血后7天、14天和28天并未持续（所有p≥0.1546）。同样，βHB治疗在前肢使用不对称性（所有p>0.45）或脑损伤体积（p = 0.3381）方面没有产生差异，脑损伤体积是本研究的主要终点。因此，我们的研究表明，脑出血后急性βHB治疗可以提供一些功能改善的早期迹象，但没有持久效果或神经保护的证据。然而，特别是考虑到纹状体炎症减轻的早期信号，其他βHB给药方案是否可能对这些以及其他神经、行为和生化参数产生有利影响仍有待测试。
