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Nanofluidic Mechanism of Brain Water Metabolism and Its Pharmacological Control

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Review Article

Nanofluidic Mechanism of Brain Water Metabolism and Its Pharmacological Control

  • Titovets E.

*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

Abstract

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.

Abbreviations:

ISS – the interstitial space; ISF –the interstitial fluid

BBB - the blood-brain barrier

AQP1- aquaporin-1

AQP4- aquaporin-4

Introduction:

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. 

Conclusion:

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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Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

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Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

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George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad

Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.

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Gomez Barriga Maria Dolores

The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.

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Lin Shaw Chin

Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.

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Maria Dolores Gomez Barriga

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.

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Dr Maria Dolores Gomez Barriga

Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.

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Dr Maria Regina Penchyna Nieto

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.

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Dr Marcelo Flavio Gomes Jardim Filho

Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”

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Zsuzsanna Bene

Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner

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Dr Susan Weiner