5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology

Aruna Sharma; Rudy J. Castellani; Mark A. Smith; Dafin Fior Muresanu; Prasanta Kumar Dey; Hari Shanker Sharma

doi:10.1016/bs.irn.2019.06.005

5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology

Aruna Sharma, Rudy J. Castellani, Mark A. Smith, Dafin Fior Muresanu, Prasanta Kumar Dey, Hari Shanker Sharma^*

^*Corresponding author for this work

Pathology

Research output: Chapter in Book/Report/Conference proceeding › Chapter

38 Scopus citations

Abstract

5-Hydroxytryptophan (5-HTP), a precursor of serotonin, is therapeutically used for several psychiatric disorders such as anxiety and depression in the clinic. However, severe side effects, including abnormal mental functions, behavioral disturbances and intolerance are associated with this treatment. 5-HTP-induced elevation of plasma and brain serotonin levels may affect blood-brain barrier (BBB) breakdown, edema formation and regional cerebral blood flow (CBF) disturbances. Breakdown of BBB to serum proteins leads to vasogenic brain edema formation and cellular injuries. However, 5-HTP-neurotoxicity is still not well known. In this investigations 5-HTP induced elevation of endogenous plasma and brain serotonin levels and its effect on BBB breakdown, edema formation neuronal injuries was examined in a rat model. Furthermore, potential role of oxidative stress and nitric oxide (NO) was evaluated. In addition, several neurochemical agents such as p-CPA (5-HT synthesis inhibitor) indomethacin (prostaglandin synthase inhibitor), diazepam (ant stress drug), cyproheptadine, ketanserin (5-HT2 receptor antagonists) and vinblastine (inhibitor of microtubule function) were examined on 5-HT neurotoxicity. Our observations suggest that 4 h after 5-HTP administrations, the endogenous serotonin levels increased by fourfold (150 mg/kg) in the plasma and brain associated with profound hyperthermia (+ 3.86 ± 0.24 °C, oxidative stress and NO upregulation. Breakdown of the BBB to Evans blue albumin (EBA) in 8 brain regions and to ^[131]Iodine in 14 brain regions was observed. The CBF exhibited marked reduction in all the brain regions examined. Brain edema and cellular injuries are present in the areas associated with BBB disruption. Drug treatments reduced the BBB breakdown, edema formation NO production and brain pathology. These observations are the first to point out that 5-HTP-neurotoxicity caused by BBB breakdown, edema formation and NO production is instrumental in causing adverse mental and behavioral abnormalities, not reported earlier.

Original language	English (US)
Title of host publication	New Therapeutic Strategies for Brain Edema and Cell Injury
Editors	Hari Shanker Sharma, Aruna Sharma
Publisher	Academic Press Inc
Pages	1-44
Number of pages	44
ISBN (Print)	9780128167540
DOIs	https://doi.org/10.1016/bs.irn.2019.06.005
State	Published - 2019

Publication series

Name	International Review of Neurobiology
Volume	146
ISSN (Print)	0074-7742
ISSN (Electronic)	2162-5514

Funding

This investigation was supported by Grants from Swedish Medical Research Council Nr. 2710; Grants from the Alzheimer's Association (IIRG-09-132087), the National Institutes of Health (R01 AG028679) and the Dr. Robert M. Kohrman Memorial Fund (M.A.S. R.J.C.); Society for Neuroprotection and Neuroplasticity (SSNN), Romania; Astra Zeneca, Mölndal; Göran Gustafsson Foundation, Stockholm, Sweden; Alexander von Humboldt Foundation, Bonn, Germany; The University Grants Commission, New Delhi, India; Indian Council of Medical Research, New Delhi, India. The skillful technical assistance of Mr. Om Prakash Gupta, Shiv Mandir Singh (Varanasi, India); Katja Deparade, Franzisca Drum, Elisabeth Scherer (Berlin, Germany); Secretarial assistance of Angela Ludwig (Berlin, Germany), Madeline Järild, Gunilla Åberg and Gunilla Tibling (Uppsala, Sweden) were highly appreciated. This investigation was supported by Grants from Swedish Medical Research Council Nr. 2710; Grants from the Alzheimer's Association (IIRG-09-132087), the National Institutes of Health (R01 AG028679) and the Dr. Robert M. Kohrman Memorial Fund (M.A.S., R.J.C.); Society for Neuroprotection and Neuroplasticity (SSNN), Romania; Astra Zeneca, Mölndal; Göran Gustafsson Foundation, Stockholm, Sweden; Alexander von Humboldt Foundation, Bonn, Germany; The University Grants Commission, New Delhi, India; Indian Council of Medical Research, New Delhi, India. The skillful technical assistance of Mr. Om Prakash Gupta, Shiv Mandir Singh (Varanasi, India); Katja Deparade, Franzisca Drum, Elisabeth Scherer (Berlin, Germany); Secretarial assistance of Angela Ludwig (Berlin, Germany), Madeline Järild, Gunilla Åberg and Gunilla Tibling (Uppsala, Sweden) were highly appreciated.

Keywords

5-Hydroxytryptamine
Blood-brain barrier
Brain edema
Diazepam
Indomethacin
Serotonin
Serotonin-2 receptors
Signal transduction mechanisms
Vesicular transport
Vinblastine

ASJC Scopus subject areas

Clinical Neurology
Cellular and Molecular Neuroscience

Access to Document

10.1016/bs.irn.2019.06.005

Cite this

Sharma, A., Castellani, R. J., Smith, M. A., Muresanu, D. F., Dey, P. K., & Sharma, H. S. (2019). 5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology. In H. S. Sharma, & A. Sharma (Eds.), New Therapeutic Strategies for Brain Edema and Cell Injury (pp. 1-44). (International Review of Neurobiology; Vol. 146). Academic Press Inc. https://doi.org/10.1016/bs.irn.2019.06.005

Sharma, Aruna ; Castellani, Rudy J. ; Smith, Mark A. et al. / 5-Hydroxytryptophan : A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology. New Therapeutic Strategies for Brain Edema and Cell Injury. editor / Hari Shanker Sharma ; Aruna Sharma. Academic Press Inc, 2019. pp. 1-44 (International Review of Neurobiology).

@inbook{e18a04d0739f45ac9efa60480956ae85,

title = "5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology",

abstract = "5-Hydroxytryptophan (5-HTP), a precursor of serotonin, is therapeutically used for several psychiatric disorders such as anxiety and depression in the clinic. However, severe side effects, including abnormal mental functions, behavioral disturbances and intolerance are associated with this treatment. 5-HTP-induced elevation of plasma and brain serotonin levels may affect blood-brain barrier (BBB) breakdown, edema formation and regional cerebral blood flow (CBF) disturbances. Breakdown of BBB to serum proteins leads to vasogenic brain edema formation and cellular injuries. However, 5-HTP-neurotoxicity is still not well known. In this investigations 5-HTP induced elevation of endogenous plasma and brain serotonin levels and its effect on BBB breakdown, edema formation neuronal injuries was examined in a rat model. Furthermore, potential role of oxidative stress and nitric oxide (NO) was evaluated. In addition, several neurochemical agents such as p-CPA (5-HT synthesis inhibitor) indomethacin (prostaglandin synthase inhibitor), diazepam (ant stress drug), cyproheptadine, ketanserin (5-HT2 receptor antagonists) and vinblastine (inhibitor of microtubule function) were examined on 5-HT neurotoxicity. Our observations suggest that 4 h after 5-HTP administrations, the endogenous serotonin levels increased by fourfold (150 mg/kg) in the plasma and brain associated with profound hyperthermia (+ 3.86 ± 0.24 °C, oxidative stress and NO upregulation. Breakdown of the BBB to Evans blue albumin (EBA) in 8 brain regions and to [131]Iodine in 14 brain regions was observed. The CBF exhibited marked reduction in all the brain regions examined. Brain edema and cellular injuries are present in the areas associated with BBB disruption. Drug treatments reduced the BBB breakdown, edema formation NO production and brain pathology. These observations are the first to point out that 5-HTP-neurotoxicity caused by BBB breakdown, edema formation and NO production is instrumental in causing adverse mental and behavioral abnormalities, not reported earlier.",

keywords = "5-Hydroxytryptamine, Blood-brain barrier, Brain edema, Diazepam, Indomethacin, Serotonin, Serotonin-2 receptors, Signal transduction mechanisms, Vesicular transport, Vinblastine",

author = "Aruna Sharma and Castellani, {Rudy J.} and Smith, {Mark A.} and Muresanu, {Dafin Fior} and Dey, {Prasanta Kumar} and Sharma, {Hari Shanker}",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

doi = "10.1016/bs.irn.2019.06.005",

language = "English (US)",

isbn = "9780128167540",

series = "International Review of Neurobiology",

publisher = "Academic Press Inc",

pages = "1--44",

editor = "Sharma, {Hari Shanker} and Aruna Sharma",

booktitle = "New Therapeutic Strategies for Brain Edema and Cell Injury",

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Sharma, A, Castellani, RJ, Smith, MA, Muresanu, DF, Dey, PK & Sharma, HS 2019, 5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology. in HS Sharma & A Sharma (eds), New Therapeutic Strategies for Brain Edema and Cell Injury. International Review of Neurobiology, vol. 146, Academic Press Inc, pp. 1-44. https://doi.org/10.1016/bs.irn.2019.06.005

5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology. / Sharma, Aruna; Castellani, Rudy J.; Smith, Mark A. et al.
New Therapeutic Strategies for Brain Edema and Cell Injury. ed. / Hari Shanker Sharma; Aruna Sharma. Academic Press Inc, 2019. p. 1-44 (International Review of Neurobiology; Vol. 146).

Research output: Chapter in Book/Report/Conference proceeding › Chapter

TY - CHAP

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T2 - A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology

AU - Sharma, Aruna

AU - Castellani, Rudy J.

AU - Smith, Mark A.

AU - Muresanu, Dafin Fior

AU - Dey, Prasanta Kumar

AU - Sharma, Hari Shanker

PY - 2019

Y1 - 2019

N2 - 5-Hydroxytryptophan (5-HTP), a precursor of serotonin, is therapeutically used for several psychiatric disorders such as anxiety and depression in the clinic. However, severe side effects, including abnormal mental functions, behavioral disturbances and intolerance are associated with this treatment. 5-HTP-induced elevation of plasma and brain serotonin levels may affect blood-brain barrier (BBB) breakdown, edema formation and regional cerebral blood flow (CBF) disturbances. Breakdown of BBB to serum proteins leads to vasogenic brain edema formation and cellular injuries. However, 5-HTP-neurotoxicity is still not well known. In this investigations 5-HTP induced elevation of endogenous plasma and brain serotonin levels and its effect on BBB breakdown, edema formation neuronal injuries was examined in a rat model. Furthermore, potential role of oxidative stress and nitric oxide (NO) was evaluated. In addition, several neurochemical agents such as p-CPA (5-HT synthesis inhibitor) indomethacin (prostaglandin synthase inhibitor), diazepam (ant stress drug), cyproheptadine, ketanserin (5-HT2 receptor antagonists) and vinblastine (inhibitor of microtubule function) were examined on 5-HT neurotoxicity. Our observations suggest that 4 h after 5-HTP administrations, the endogenous serotonin levels increased by fourfold (150 mg/kg) in the plasma and brain associated with profound hyperthermia (+ 3.86 ± 0.24 °C, oxidative stress and NO upregulation. Breakdown of the BBB to Evans blue albumin (EBA) in 8 brain regions and to [131]Iodine in 14 brain regions was observed. The CBF exhibited marked reduction in all the brain regions examined. Brain edema and cellular injuries are present in the areas associated with BBB disruption. Drug treatments reduced the BBB breakdown, edema formation NO production and brain pathology. These observations are the first to point out that 5-HTP-neurotoxicity caused by BBB breakdown, edema formation and NO production is instrumental in causing adverse mental and behavioral abnormalities, not reported earlier.

AB - 5-Hydroxytryptophan (5-HTP), a precursor of serotonin, is therapeutically used for several psychiatric disorders such as anxiety and depression in the clinic. However, severe side effects, including abnormal mental functions, behavioral disturbances and intolerance are associated with this treatment. 5-HTP-induced elevation of plasma and brain serotonin levels may affect blood-brain barrier (BBB) breakdown, edema formation and regional cerebral blood flow (CBF) disturbances. Breakdown of BBB to serum proteins leads to vasogenic brain edema formation and cellular injuries. However, 5-HTP-neurotoxicity is still not well known. In this investigations 5-HTP induced elevation of endogenous plasma and brain serotonin levels and its effect on BBB breakdown, edema formation neuronal injuries was examined in a rat model. Furthermore, potential role of oxidative stress and nitric oxide (NO) was evaluated. In addition, several neurochemical agents such as p-CPA (5-HT synthesis inhibitor) indomethacin (prostaglandin synthase inhibitor), diazepam (ant stress drug), cyproheptadine, ketanserin (5-HT2 receptor antagonists) and vinblastine (inhibitor of microtubule function) were examined on 5-HT neurotoxicity. Our observations suggest that 4 h after 5-HTP administrations, the endogenous serotonin levels increased by fourfold (150 mg/kg) in the plasma and brain associated with profound hyperthermia (+ 3.86 ± 0.24 °C, oxidative stress and NO upregulation. Breakdown of the BBB to Evans blue albumin (EBA) in 8 brain regions and to [131]Iodine in 14 brain regions was observed. The CBF exhibited marked reduction in all the brain regions examined. Brain edema and cellular injuries are present in the areas associated with BBB disruption. Drug treatments reduced the BBB breakdown, edema formation NO production and brain pathology. These observations are the first to point out that 5-HTP-neurotoxicity caused by BBB breakdown, edema formation and NO production is instrumental in causing adverse mental and behavioral abnormalities, not reported earlier.

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KW - Blood-brain barrier

KW - Brain edema

KW - Diazepam

KW - Indomethacin

KW - Serotonin

KW - Serotonin-2 receptors

KW - Signal transduction mechanisms

KW - Vesicular transport

KW - Vinblastine

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Sharma A, Castellani RJ, Smith MA, Muresanu DF, Dey PK, Sharma HS. 5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology. In Sharma HS, Sharma A, editors, New Therapeutic Strategies for Brain Edema and Cell Injury. Academic Press Inc. 2019. p. 1-44. (International Review of Neurobiology). doi: 10.1016/bs.irn.2019.06.005

5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology

Abstract

Publication series

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Keywords

ASJC Scopus subject areas

Access to Document

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