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Review Article | DOI: https://doi.org/10.31579/2693-7247/094
Department of Neurosurgery of Republican Research and Clinical Center of Neurology and Neurosurgery, Minsk, Belarus.
*Corresponding Author: Department of Neurosurgery of Republican Research and Clinical Center of Neurology and Neurosurgery, Minsk, Belarus.
Citation: Titovets E, (2022). Nanofluidic Mechanism of Brain Water Metabolism and Its Pharmacological Control. J Pharmaceutics and Pharmacology Research. 5(8), DOI: 10.31579/2693-7247/094
Copyright: @ 2022 Titovets E, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Received: 08 August 2022 | Accepted: 29 September 2022 | Published: 10 October 2022
Keywords: brain water metabolism; diffusion barrier theory; nanofluidic mechanism of brain water metabolism; AQP4-targeted drug therapy
Brain water metabolism is involved in realization of a broad spectrum of vitally important physiological functions of the brain. Its disorders in various pathologies often lead to serious complications and death. Finding ways of pharmacological control of brain water metabolism is important to therapy of many conditions in neurology and neurosurgery. At present, there are the two mutually excluding basic views on brain water metabolism making it a center of theoretical controversy. A conventional approach affirms that the brain nanodimentional extracellular space presents a diffusion barrier to water movement. An interdisciplinary approach suggests that a slip-flow mechanism governs water movement there in the extracellular space that presents an integral part of the brain nanofluidic domain. This review centers on the nanofluidic mechanism of brain water metabolism and the AQP4-targeted drug control of brain water metabolism. The information presented here might be used in a neurobiological research, development of the AQP4-targeted drug therapy, optimization of intrathecal drug delivery, in a research on the therapy of the brain water metabolism disorders.
ISS – the interstitial space; ISF –the interstitial fluid
BBB - the blood-brain barrier
AQP1- aquaporin-1
AQP4- aquaporin-4
The red arrow indicates the direction of the blood flow in the capillary. The dotted blue line with AQP4 present this aquaporin in the astrocyte endfeet membrane enveloping the capillary. The functionally different parts of the capillary are designated as FS (the Filtration Section), OS (the
Oscillatory Section), and RS (the Reabsorption Section). The blue arrows, with the rate symbols “Jv”, “±Jv”, and –Jv”, indicate the direction of the water flows in the respective sections. The oncotic pressure in the capillary and the interstitial fluid is πC and πISF, respectively. Hydrostatic pressure is pa at the arterial end of the capillary and pv at the venule end. The intracranial pulsatory pressure is f(t). The square brackets indicate the nanofluidic domain. Note that the schematic is not drawn to scale and does not represent the true ratio between capillary diameter and the capillary length [8] .
Figure 1: Nanofluidic mechanism of brain water metabolism
This interdisciplinary approach opens new fascinating perspectives in elucidating the so far concealed features of the brain water metabolism with important physiological implications.
Having adopted the nanofluidic approach and employed computer simulation technique, we have studded, in some detail, the brain water metabolism and related issues [8],[9],[10], [11],[12],[13],[14],[15].
The nanofluidic model of brain water metabolism is built on the following assumptions:
the brain nondimensional extracellular space presents a nanofluidic domain where water movement there governed by the slip-flow mechanism; aquaporin AQP4 ensures kinetic control over water movement between the blood and the brain extracellular space;the overall fluid transfer between the capillary blood and the interstitial fluid is isosmotic;the pulsatory intracranial pressure presents a driving force behind the isosmotic fluid exchange between the capillaries and the interstitial space [8].
A study of brain water metabolism, using a new approach, makes it possible to observe its many features relevant to brain physiology and pathological situations. It has been demonstrated the way AQP4 polarization in the astrocyte endfeet membrane affects the radial water fluxes. The model made it possible to assess quantitatively the influence of elevated intracranial hydrostatic pressure and elevated venous hydrostatic pressure on the transcapillary water exchange. An interesting feature of the model is that it makes possible to study mass-transfer events in the brain tissue. Thus it has been employed to study tissue oxygenation, transfer of carbon dioxide and glucose. The model might be used to study the effects of pharmacological modulators of AQP4 activity (the BBB permeability). The model demonstrates an intimate connection between brain water metabolisms and heart activity.
Brain edema brings about an increased intracranial pressure, effects cerebral circulation, causes brain hypoxia and a number of pathophysiological changes leading to severe neurological disorders and death. Cerebral edema occurs in a wide range of pathologies like traumatic brain injury, the stroke, hemorrhages, hydrocephalus, brain tumors, etc. The brain edema may also arise from the causes originated outside the brain: postoperative trauma, hemodynamic and hormonal-electrolyte disorders; cardiac, hepatic, renal, respiratory insufficiency; decompensated endocrine pathology, etc. Clinical practice demonstrates that there are still remain unresolved problems about the correction of the water metabolism disorders [16] , [17]. There are also remain some controversies abbot understanding, at the basic level, the mechanism of the brain water metabolism `
This metabolism has been a subject of close attention of researchers and of hot debates. To date, there is remain controversy about the issue. It stands in the way of the development of the effective means of the treatment of the brain water metabolism disorders.
The role of the choroidal plexus in the brain water metabolism has been scrutinized and subjected to criticism as untenable in the light of the latest basic and clinical research evidence [18] [19]. Acceding to an alternative theory, the main participants in the cerebral water exchange are the capillaries of the whole brain parenchyma, and not the choroidal plexus [20].
Water metabolism is associated with the activity of the quantitatively predominant and functionally most important aquaporin AQP4. This aquaporin is expressed in large quantities, as the two-dimensional orthogonal structures, in the plasma membrane of the astrocyte endfeet enveloping the capillaries [21], [22]. AQP4 controls the transfer of water across the BBB. Controlling the water movement between the blood and the interstitial space, it plays an important role in brain physiology, as well as in the development of pathological reactions leading to edema [23] [24].
AQP4 is viewed a molecular target for drug action directed at correction the disorders of brain water metabolism. Figure 2 demonstrates the results of AQP4 inhibition on water flow into brain parenchyma.
Figure 2. Aquaporin AQP4 inhibition and water transfer across the BBB into brain parenchyma.
A.No AQP4 inhibition. B. 50% inhibition of AQP4 activity C. 75% inhibition of AQP4 activity
1. The total racial water volume transferred over a cardiac cycle.
2. The racial water volume transferred over the systolic phase of the cardiac cycle.
3. The racial water volume transferred over the diastolic phase of the cardiac cycle.
New knowledge makes it possible to outline promising approaches in the treatment of the brain water metabolism disorders [3], [9],[12],[25]. The pharmacological arsenal of medicines currently used to correct disorders of cerebral water metabolism and combat brain edema represents a complex, which includes means of osmotherapy (mannitol, hypertonic sodium chloride solution), diuretics (furosemide, bumetanide) and other drugs with different mechanisms of action (corticosteroids, testosterone, dexamethasone, propofol, piroxicam, acetazolamide, etc.).
The osmotherapy is used to provide an osmotic pressure gradient between blood and the brain fluids and to ensure directed water flow from the brain tissues into the systemic circulation. Diuretics serve the same purpose.
The success of osmotherapy depends on water permeability of the BBB controlled by AQP4. Numerous studies have shown that the level of expression and the degree of polarization of AQP4 in the BBB structures are labile and depend on many physiological factors. Significant changes in the activity of AQP4 are observed in pathologies [26].
The concept according to which aquaporins present molecular targets for drugs is very attractive and practically important [27], [28], [29], [30] . In view of this, much research has been carried out to study the action of drugs on aquaporin activity.
The Table shows the effects of some drugs, used in the treatment brain edema and water metabolism disorders, on the activity of aquaporins AQP1 and AQP4.
Table. Pharmacological modulators of AQP1 and AQP4 activity
Chemical modulators of aquaporins penetrating into the cell produce either an inhibitory or an activating effect on a specific aquaporin. The same aquaporin in different tissues may be involved in implementation of different physiological functions and thus be involved in the appearance of different responses at the organ level. For example, inhibition of AQP1 in the collecting tubes of the kidney results in increased diuresis. On the other hand, AQP1 inhibitors have no effect on water permeability of the BBB. This asks for comprehensive information about drug action on the activity of a respective aquaporin and careful evaluations of their pharmacological effects.
There is always a problem to solve concerning a pharmacological modulator reaching its target molecule to produce therapeutic effect. One of the approaches to solve this problem is development of prodrugs. Thus, for this purpose, a prodrug, an acetoxy-methyl derivative of furosemide, has been synthesized that, in the process of bioconversion inside the cell, releases furosemide, an AQP4 antagonist. A similar approach has been used to increase permeability of bumetanide [43].
From the nanofluidic mechanism of the brain water metabolism, there follow some practical recommendations for the treatment of brain edema as far as the BBB water permeability is concerned. In particular, it is important to employ a pharmacological control of AQP4 activity in respect to the phases of brain edema. At the early stages, it is reasonable to inhibit AQP4 activity to reduce water flow into the brain and thus preventing further development of edema. The same tactics might be employed for premedication to prevent formation of brain edema, in view of upcoming operation on the brain, etc.
However, in fully developed edema, when there is a problem of removing fluid excess from the brain tissues, the use of AQP4 inhibitors should be avoided. By preventing water outflow, pharmacological inhibitors will negatively affect the effectiveness of osmotherapy, contribute to persistence of edema and negatively reflect upon neurological status of the patient.
At present, brain water metabolism has become a center of theoretical controversy. There are two mutually excluding basic views on the events underlying the workings of brain water metabolism. According to a conventional approach, brain nanodimentional extracellular space presents a diffusion barrier to water movement. Contrary to this theory, an interdisciplinary approach suggests water movement there as a slip-flow process that would result in appearance of water fluxes in the extracellular space. The central argument to support the latter theory is that the extracellular space is an integral part of the brain nanofluidic domain.
The concept of diffusion barrier is incompatible with that of the nanofluidic mechanism of brain water metabolism. The BBB separates the two water moieties: that of the blood, governed by convection, and that of the water in the nanodimentional extracellular space, governed by diffusion, according to the diffusion barrier theory. Introducing diffusion is tantamount to making kinetically redundant AQP that otherwise controls water transfer over the BBB. This will be the case because case the limiting step would be shifted from AQP4 to the diffusion barrier of the extracellular space. The diffusion barrier theory makes invisible all those interesting findings in the mechanism of brain water metabolism revealed through the nanofluidic approach.
It should be observed that nanofluidic mechanism of brain water metabolism, contrary to the diffusion barrier theory, opens wide possibilities for developing the ways of pharmacological control of brain water metabolism.
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