Pathophysiological implications of neurovascular P450 in brain disorders

Ghosh, Chaitali; Hossain, Mohammed Kamal; Solanki, Jesal; Dadas, Aaron; Marchi, Nicola; Janigro, Damir

doi:10.1016/j.drudis.2016.06.004

Cited by 53 publications

(37 citation statements)

References 116 publications

(181 reference statements)

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“…Dopamine and tyramine are metabolized by CYP2D6, and neurosteroid metabolism also occurs via the isozymes of the CYP3A subgroup. 50 , 51 Studying CBD interaction with neurovascular cytochrome P450 enzymes might also offer new mechanisms of action. It could be possible that CBD-mediated CYP2D6 inhibition increases dopamine levels in the brain, which could help to explain the positive CBD effects in addiction/withdrawal scenarios and might support its 5HT (=serotonin) elevating effect in depression.…”

Section: Acute Clinical Datamentioning

confidence: 99%

An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies

Iffland

Grotenhermen

2017

Cannabis and Cannabinoid Research

504

358

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Introduction: This literature survey aims to extend the comprehensive survey performed by Bergamaschi et al. in 2011 on cannabidiol (CBD) safety and side effects. Apart from updating the literature, this article focuses on clinical studies and CBD potential interactions with other drugs.Results: In general, the often described favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. In comparison with other drugs, used for the treatment of these medical conditions, CBD has a better side effect profile. This could improve patients' compliance and adherence to treatment. CBD is often used as adjunct therapy. Therefore, more clinical research is warranted on CBD action on hepatic enzymes, drug transporters, and interactions with other drugs and to see if this mainly leads to positive or negative effects, for example, reducing the needed clobazam doses in epilepsy and therefore clobazam's side effects.Conclusion: This review also illustrates that some important toxicological parameters are yet to be studied, for example, if CBD has an effect on hormones. Additionally, more clinical trials with a greater number of participants and longer chronic CBD administration are still lacking.

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Section: Acute Clinical Datamentioning

confidence: 99%

An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies

Iffland

Grotenhermen

2017

Cannabis and Cannabinoid Research

504

358

View full text Add to dashboard Cite

show abstract

“…− , OH − ) via abnormal uncoupling of the normal metabolic pathways due to hypoxia-specific signals. [75][76][77] Lysyl oxidases (LOXs) Protein-lysine 6-oxidase, also known as LOX, produces H 2 O 2 as a byproduct during crosslinking between cell-matrix protein elastin and collagen using the lysyl tyrosylquinone cofactor. 78 The enzyme is regulated by Hif-1 or Hif-2 and generates ROS and induces metastasis and cell-matrix adhesion via the FAK/Src signaling pathway in both ischemia and glioma.…”

Section: Peroxisomesmentioning

confidence: 99%

The interrelationship between cerebral ischemic stroke and glioma: a comprehensive study of recent reports

Ghosh

Chakraborty

Sarkar

et al. 2019

Sig Transduct Target Ther

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Glioma and cerebral ischemic stroke are two major events that lead to patient death worldwide. Although these conditions have different physiological incidences,~10% of ischemic stroke patients develop cerebral cancer, especially glioma, in the postischemic stages. Additionally, the high proliferation, venous thrombosis and hypercoagulability of the glioma mass increase the significant risk of thromboembolism, including ischemic stroke. Surprisingly, these events share several common pathways, viz. hypoxia, cerebral inflammation, angiogenesis, etc., but the proper mechanism behind this co-occurrence has yet to be discovered. The hypercoagulability and presence of the D-dimer level in stroke are different in cancer patients than in the noncancerous population. Other factors such as atherosclerosis and coagulopathy involved in the pathogenesis of stroke are partially responsible for cancer, and the reverse is also partially true. Based on clinical and neurosurgical experience, the neuronal structures and functions in the brain and spine are observed to change after a progressive attack of ischemia that leads to hypoxia and atrophy. The major population of cancer cells cannot survive in an adverse ischemic environment that excludes cancer stem cells (CSCs). Cancer cells in stroke patients have already metastasized, but early-stage cancer patients also suffer stroke for multiple reasons. Therefore, stroke is an early manifestation of cancer. Stroke and cancer share many factors that result in an increased risk of stroke in cancer patients, and vice-versa. The intricate mechanisms for stroke with and without cancer are different. This review summarizes the current clinical reports, pathophysiology, probable causes of co-occurrence, prognoses, and treatment possibilities.

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“…Neural CYP enzymes are considered to play important physiological roles in maintaining neural homeostasis through the biosynthesis and degradation of biologically essential endogenous compounds because previous studies demonstrated that CYP enzyme levels in specific neurons may be as high as or higher than those in hepatocytes and CYP expression is typically distributed to specific populations of neurons (Miksys et al, 2000(Miksys et al, , 2003. The characterization of brain and/or neural CYP enzymes and their localization as well as the identification of endogenous substrates and their metabolic endproducts will provide a better understanding of the role of CYP enzymes in brain physiology, development, and diseases (Ghosh et al, 2016;Toselli et al, 2016). It may also be qualitatively and quantitatively different from that in the liver due to differences in expression or to the presence of unique enzymes in the brain and particular neurons (Stamou et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Expression levels of 39 Cyp mRNAs in the mouse brain and neuroblastoma cell lines, C-1300N18 and NB2a – strong expression of Cyp1b1

Yamaori

Jiang

Maeda

et al. 2017

Fundam. Toxicol. Sci.

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-An analysis of mRNA levels of 39 Cyp enzymes in the mouse brain and neuroblastoma cell lines, C-1300N18 and NB2a was performed using a real-time reverse transcriptase-polymerase chain reaction. Relative expression levels were quantified by normalized β-actin levels, and compared to the mRNA expression level of the cannabinoid receptor (CB1R), which is abundantly expressed in the mouse brain. Mean 2^-ddCts of CB1R in mouse brain, C-1300N18, and NB2a cells were 1.043, 1.003, and 1.005, respectively. Among Cyp mRNAs in the mouse brain, Cyp1b1 mRNA was the most abundantly expressed (2^-ddCt = 0.310), followed by Cyp46a1 mRNA (0.246). The other Cyp mRNAs moderately expressed (0.011 ~ 0.117) were Cyp1a1, 1a2, 2b10, 2c29, 2c50, 2d9, 2d10, 2d12, 2d22, 2d26, 3a11, 3a41, 4f14, 4f15, 4f16, and 4x1. On the other hand, 10 out of 39 Cyp mRNAs (Cyp 2b9, 2b13, 2b19, 2c37, 2c38, 2c55, 3a44, 4a12, 4a14, and 4f18) were not detectable (2^-ddCt < 0.001). In the neuroblastoma cell lines, C-1300N18 and NB2a, Cyp1b1 mRNA was also the most abundant and preferentially expressed, and relative expression levels to CB1R were 4.674 and 5.084, respectively. Thirteen other Cyp mRNAs (Cyp1a1, 1a2, 2a5, 2b10, 2c44, 2c50, 2c55, 2d10, 2d22, 3a11, 4f13, 4f15, and 4f16) were detected in the neuroblastoma cell lines, whereas 17 Cyp mRNAs (Cyp2c29, 2c37, 2c39, 2c40, 2d12, 2d34, 2e1, 3a16, 3a25, 3a41, 3a44, 4a10, 4a12, 4a14, 4f14, 4x1, and 46a1) were not under the current conditions. The pattern of Cyp mRNA expression was similar for both neuroblastoma cell lines. The present results provide fundamental and useful information on the significance of particular Cyp enzymes in the mouse brain and neuroblastoma cell lines, C-1300N18 and NB2a, which may be valuable tools for investigations on the neural expression and function of Cyp1b1.

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Pathophysiological implications of neurovascular P450 in brain disorders

Cited by 53 publications

References 116 publications

An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies

An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies

The interrelationship between cerebral ischemic stroke and glioma: a comprehensive study of recent reports

Expression levels of 39 Cyp mRNAs in the mouse brain and neuroblastoma cell lines, C-1300N18 and NB2a – strong expression of Cyp1b1

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