Consideration of Kinase Inhibitors for the Treatment of Hydrocephalus

Abstract

Hydrocephalus is a devastating condition characterized by excess cerebrospinal fluid (CSF) in the brain. Currently, the only effective treatment is surgical intervention, usually involving shunt placement, a procedure prone to malfunction, blockage, and infection that requires additional, often repetitive, surgeries. There are no long-term pharmaceutical treatments for hydrocephalus. To initiate an intelligent drug design, it is necessary to understand the biochemical changes underlying the pathology of this chronic condition. One potential commonality in the various forms of hydrocephalus is an imbalance in fluid–electrolyte homeostasis. The choroid plexus, a complex tissue found in the brain ventricles, is one of the most secretory tissues in the body, producing approximately 500 mL of CSF per day in an adult human. In this manuscript, two key transport proteins of the choroid plexus epithelial cells, transient receptor potential vanilloid 4 and sodium, potassium, 2 chloride co-transporter 1, will be considered. Both appear to play key roles in CSF production, and their inhibition or genetic manipulation has been shown to affect CSF volume. As with most transporters, these proteins are regulated by kinases. Therefore, specific kinase inhibitors are also potential targets for the development of pharmaceuticals to treat hydrocephalus.

Transient ischemic stroke triggers sustained damage of the choroid plexus blood-CSF barrier

“…Evidence for the disintegration of the barrier was also supported by the corresponding loss of TJ proteins, ZO-1, claudin 5, and claudin-1, found between the CPECs (Figures 4, 5). An important component of the ChP with relevance to this is SPAK-NKCC1 protein complex, the ion transport regulatory apparatus that is responsible for the ChP's CSF production and clearance (Steffensen et al, 2018;Gregoriades et al, 2019;Blazer-Yost, 2023). NKCC1 is regulated by SPAK kinase, which phosphorylates it for activation after generating a NKCC1-SPAK complex (Blazer-Yost, 2023).…”

“…A vital ion transporter for this process is the sodium-potassium-chlorine cotransporter isoform 1 (NKCC1), which is expressed abundantly on the apical membrane of CPECs (Gregoriades et al, 2019). Coupling with the function of the water channel AQP1, NKCC1-mediated Na + , K + , Cl − flux has been posited to contribute to the CSF secretion (Steffensen et al, 2018;Blazer-Yost, 2023). Pathological stimulation of ChP SPAK-NKCC1 protein complex causes LPS-or hemorrhagic hydrocephalus in adult rats (Robert et al, 2023).…”

“…However, in the PHH model, overexpression of the NKCC1 protein prevents ventriculomegaly by enhancing CSF clearance and CSF K + uptake (Xu et al, 2021;Sadegh et al, 2023). This suggests that the direction of NKCC1-mediated electrolyte and water transport can be in the "reverse" mode which redistributes CSF ions via the CPEC uptake (Blazer-Yost, 2023). We previously reported that ischemic stroke in mice stimulates the CPEC apical membrane expression of SPAK-NKCC1 complex at 24 h post-ischemic stroke, which is associated with loss of the blood-CSF barrier integrity and increased immune cell infiltration into the ChP (Wang et al, 2022).…”

Understanding and Modeling the Pathophysiology of Hydrocephalus: In Search of Better Treatment Options

“…It was previously reported that around 600 molecules could be moved by NKCC1 [123], but recent studies suggest that the transporter only moves around 86 water molecules [124]. The NKCC1 is not only expressed on the CPe, but in many tissues where it is important for maintaining cell volume [125][126][127]. When NKCC1 is mutated or knocked out it causes severe disease symptoms [128].…”

“…One explanation for the apparently contradictory behavior of this channel is that it can adapt to maintain homeostasis. The ion channel seems to be able to move ions to either side of the membrane depending on the external/internal environment [121,127]. Additional studies will be required to determine the factors involved in the control and mechanism of NKCC1 in the CPe.…”