Hydroxyethylstarch revisited for acute brain injury treatment

Abstract

Infusion of the colloid hydroxyethylstarch has been used for volume substitution to maintain hemodynamics and microcirculation after e.g., severe blood loss. In the last decade it was revealed that hydroxyethylstarch can aggravate acute kidney injury, especially in septic patients. Because of the serious risk for critically ill patients, the administration of hydroxyethylstarch was restricted for clinical use. Animal studies and recently published in vitro experiments showed that hydroxyethylstarch might exert protective effects on the blood-brain barrier. Since the prevention of blood-brain barrier disruption was shown to go along with the reduction of brain damage after several kinds of insults, we revisit the topic hydroxyethylstarch and discuss a possible niche for the application of hydroxyethylstarch in acute brain injury treatment.

Keywords: acute subarachnoid hemorrhage; astrocyte; chronic kidney disease; delayed cerebral ischemia; microglia; neurovascular unit; osmotic pressure; pericyte; stroke; traumatic brain injury.

Figure 1

Summary of proposed mechanistic processes responsible for blood-brain barrier (BBB) breakdown during cerebral ischemia and hypotheses about effects of hydroxyethylstarch (HES) in BBB restoration. (A) In the healthy BBB brain capillary endothelial cells form the main component of the barrier. Intercellular gaps are sealed by tight junction strands, which prevent an unspecific permeation of mainly hydrophilic compounds into the central nervous system (CNS). A huge array of mechanisms control the transcellular transport across the BBB and subsequent entry of substances into the CNS. Transporter proteins could be classified in ATP-binding cassette (ABC) transporters and solute carrier (SLC) transporters with 48 or almost 400 member proteins, respectively. These transporters regulate the transcellular permeation of compounds by preventing (efflux) or enabling their entry (influx). Most prominent efflux transporters are ABCB1 (P-gp, P-gylcoprotein), ABCG2 (BCRP, breast cancer resistance protein) and ABCCs (MRPs, multidrug resistance associated proteins), whereas especially nutrient transporters such as SLC2A1 (GLUT-1) or SLC7A5 (LAT-1) belong to the best studied influx carriers. Bigger molecules such as peptides, proteins, particles or even cells can use receptor–or adsorption mediated transcytosis (RMT, AMT) pathways. Microenvironmental stimuli can strongly regulate the function of brain capillary endothelial cells. These stimuli could be molecules secreted, for example, by neighboring cells such as astrocytes (AC) or pericytes (PC) or physical forces such as shear stress induced by blood flow. Brain capillary endothelial cells share the same basal lamina (BL) with pericytes, whereas astrocytes are separated by an additional extracellular matrix layer and cover the majority of the surface of blood capillaries from the CNS side (Abbott et al., 2006, 2010). Within the neurovascular unit the interaction of brain capillary endothelial cells is also proposed with further CNS cells such as microglia (MC), oligodendrocytes (OD) and neurons (N), whereas the interplay with cells in blood such as red blood cells (RBC), macrophages (MP), neutrophils (NP) or platelets (P) is recognized as important but understudied. (B) During cerebral ischemia it was shown that BBB permeability is increased in several phases based on different mechanisms. It is proposed that BBB disruption is causally linked to brain edema formation and development of sequelae after stroke and traumatic brain injury. Therefore, it was hypothesized that the BBB could be a promising target for therapeutic strategies against brain injuries (Thal and Neuhaus, 2014). Some of the mechanisms include opening of the tight junctions which could be linked to phosphorylation of the myosin-light chains, increase of intracellular calcium (Ca²⁺)_i and formation of reactive oxygen species (ROS). But also active transporter systems are regulated leading to an altered transcellular permeability, pericytes can lose their close contacts to brain capillary endothelial cells which is proposed to be correlated with an increased transcellular transcytosis rate, and immune cell entry is enabled preferentially at the post-capillary venules. Released tissue-type plasminogen activator (t-PA) and subsequently activated matrix metalloproteinases (MMPs) degrade proteins including tight junction proteins such as Occludin. Due to the lowered availability of glucose during cerebral ischemia, brain endothelial cells upregulate the expression and functionality of glucose transporters such as SLC2A1 (Glut-1) which can also contribute to brain edema formation by the suggested co-transport of water molecules (MacAulay and Zeuthen, 2010). Moreover, ion channel functionality is changed disturbing ion and water homeostasis (O’Donnell, 2014). Concordantly to these detrimental processes autophagy in brain endothelial cells is increased under ischemic conditions (Kim et al., 2020). (C) In relation to these adverse molecular mechanisms at the BBB under ischemic conditions, data of effects of HES (symbolized with pink circles) in different in vitro and in vivo models suggest that HES might have the potential to counteract BBB damage. For example, HES can decrease activity of mitochondrial dehydrogenases (mDHs), ROS formation and stabilize paracellular permeability (Gerhartl et al., 2020a). Yet unpublished data from our own lab suggested that autophagy or single steps of autophagy could be modified by HES. Another important point, which should be investigated in detail in the near future, is the interplay of HES with glucose dependent processes. HES is based on modified glucose units, and thus possibly interact with uptake and metabolic pathways of glucose maybe competing about the same interaction and binding sites with glucose itself. This might lead to an altered glucose uptake and/or metabolism such as glycolysis or subsequent respiratory chain which is also linked to the formation of ROS. Moreover, the interplay of AMP-activated protein kinase (AMPK) as intracellular energy sensor within the cell and the mechanistic target of rapamycin (mTOR) could be concerned and presents a link to autophagy. However, the detailed mechanisms and interactions have still to be resolved.