Haptoglobin Treatment for Aneurysmal Subarachnoid Hemorrhage: Review and Expert Consensus on Clinical Translation

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body's first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin's anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation

Cerebrospinal fluid leakage after posterior fossa surgery may impair brain metabolite clearance

International audienceCiliary neurotrophic factor (CNTF) is neuroprotective against multiple pathologic conditions including metabolic impairment, but the mechanisms are still unclear. To delineate CNTF effects on brain energy homeostasis, we performed a multimodal imaging study, combining in vivo proton magnetic resonance spectroscopy, high-performance liquid chromatography analysis, and in situ glutamate imaging by chemical exchange saturation transfer. Unexpectedly, we found that CNTF expression through lentiviral gene transfer in the rat striatum significantly decreased the levels of neuronal metabolites ( N-acetyl-aspartate, N-acetyl-aspartyl-glutamate, and glutamate). This preclinical study shows that CNTF remodels brain metabolism, and suggests that decreased levels of neuronal metabolites may occur in the absence of neuronal dysfunction