Cerebral influx of Na+ and Cl− as the osmotherapy-mediated rebound response in rats

Abstract

BackgroundCerebral edema can cause life-threatening increase in intracranial pressure. Besides surgical craniectomy performed in severe cases, osmotherapy may be employed to lower the intracranial pressure by osmotic extraction of cerebral fluid upon intravenous infusion of mannitol or NaCl. A so-called rebound effect can, however, hinder continuous reduction in cerebral fluid by yet unresolved mechanisms.MethodsWe determined the brain water and electrolyte content in healthy rats treated with osmotherapy. Osmotherapy (elevated plasma osmolarity) was mediated by intraperitoneal injection of NaCl or mannitol with inclusion of pharmacological inhibitors of selected ion-transporters present at the capillary lumen or choroidal membranes. Brain barrier integrity was determined by fluorescence detection following intravenous delivery of Na+-fluorescein.ResultsNaCl was slightly more efficient than mannitol as an osmotic agent. The brain water loss was only ~ 60% of that predicted from ideal osmotic behavior, which could be accounted for by cerebral Na+ and Cl− accumulation. This electrolyte accumulation represented the majority of the rebound response, which was unaffected by the employed pharmacological agents. The brain barriers remained intact during the elevated plasma osmolarity.ConclusionsA brain volume regulatory response occurs during osmotherapy, leading to the rebound response. This response involves brain accumulation of Na+ and Cl− and takes place by unresolved molecular mechanisms that do not include the common ion-transporting mechanisms located in the capillary endothelium at the blood–brain barrier and in the choroid plexus epithelium at the blood–CSF barrier. Future identification of these ion-transporting routes could provide a pharmacological target to prevent the rebound effect associated with the widely used osmotherapy.

SPECT/CT imaging reveals CNS-wide modulation of glymphatic cerebrospinal fluid flow by systemic hypertonic saline

“…MRI demonstrated a consistent decrease in the brain volume after HTS administration that was accompanied with an equivalent increase in CSF volume. These results together with observed increase in plasma and CSF osmolality support earlier findings that systemic HTS dehydrates the brain by drawing fluid from the brain parenchyma into blood and CSF following along the altered osmotic gradient ( Järvelä et al., 2003 ; Oernbo et al., 2018 ; Plog et al., 2018 ). We hypothesized these notable physiological alterations to be reflected in the behavior of the animals, but found the behavioral effects of HTS to be modest, limited to a transient decrease in locomotion.…”

Cerebrospinal fluid production by the choroid plexus: a century of barrier research revisited

“…The cerebral endothelium, however, express ‘epithelia-like’ polarized distribution of various transport proteins, which could partake in fluid secretion, for reviews, see [ 69 – 72 ]. However, the slow penetration of 22/24 Na + across the endothelial layer into the adjacent parenchyma [ 50 , 73 ], and the inability of general inhibitors of CSF secretion and of various Na + -coupled endothelial transport mechanisms to prevent Na + and fluid entry into the brain [ 48 , 74 ], suggest that the cerebral vasculature may provide but a minor contribution to CSF secretion under physiological circumstances.…”

Resuscitation Strategies for Traumatic Brain Injury

“…Among the two most common agents used, HTS appears to be more effective in reducing ICP burden, but this has not led to significant differences in outcomes [82,[84][85][86]. Preclinical data from Oernbo et al also demonstrated that hyperosmolar NaCl solution induced a greater osmotic response than mannitol [87].…”