Overview of blood-brain barrier dysfunction in methamphetamine abuse

Pang, Lei; Wang, Yun

doi:10.1016/j.biopha.2023.114478

Cited by 11 publications

(3 citation statements)

References 96 publications

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“…Methamphetamine (METH) is a widely used psychostimulant substance that readily crosses the blood-brain barrier (BBB) and enters the brain. 1 Adverse consequences resulting from its abuse have emerged as a worldwide concern, 2 as it impairs the functionality and cognitive processes of the central nervous system (CNS). 2,3 METH disrupts the normal neuronal activity in the brain by enhancing the release of neurotransmitters such as dopamine, serotonin, and glutamate.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cell‐derived exosomes improve neurogenesis and cognitive function of mice with methamphetamine addiction: A novel treatment approach

Fallahi,

Zangbar,

Farajdokht

et al. 2024

CNS Neurosci Ther

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BackgroundMethamphetamine (METH) is a psychostimulant substance with highly addictive and neurotoxic effects, but no ideal treatment option exists to improve METH‐induced neurocognitive deficits. Recently, mesenchymal stem cells (MSCs)‐derived exosomes have raised many hopes for treating neurodegenerative sequela of brain disorders. This study aimed to determine the therapeutic potential of MSCs‐derived exosomes on cognitive function and neurogenesis of METH‐addicted rodents.MethodsMale BALB/c mice were subjected to chronic METH addiction, followed by intravenous administration of bone marrow MSCs‐derived exosomes. Then, the spatial memory and recognition memory of animals were assessed by the Barnes maze and the novel object recognition test (NORT). The neurogenesis‐related factors, including NeuN and DCX, and the expression of Iba‐1, a microglial activation marker, were assessed in the hippocampus by immunofluorescence staining. Also, the expression of inflammatory cytokines, including TNF‐α and NF‐κB, were evaluated by western blotting.ResultsThe results showed that BMSCs‐exosomes improved the time spent in the target quadrant and correct‐to‐wrong relative time in the Barnes maze. Also, NORT's discrimination index (DI) and recognition index (RI) were improved following exosome therapy. Additionally, exosome therapy significantly increased the expression of NeuN and DCX in the hippocampus while decreasing the expression of inflammatory cytokines, including TNF‐α and NF‐κB. Besides, BMSC‐exosomes down‐regulated the expression of Iba‐1.ConclusionOur findings indicate that BMSC‐exosomes mitigated METH‐caused cognitive dysfunction by improving neurogenesis and inhibiting neuroinflammation in the hippocampus.

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Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cell‐derived exosomes improve neurogenesis and cognitive function of mice with methamphetamine addiction: A novel treatment approach

Fallahi,

Zangbar,

Farajdokht

et al. 2024

CNS Neurosci Ther

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show abstract

“…Additionally, there is a strong premise that substance use adversely impacts the BBB 61,66,67,[135][136][137][138][139][140][141][142][143][144][145][146] . Most studies focused primarily on BBB integrity, transendothelial electrical resistance, and permeability.…”

Section: Discussionmentioning

confidence: 99%

Cocaine Regulates Antiretroviral Therapy CNS Access Through Pregnane-X Receptor-Mediated Drug Transporter and Metabolizing Enzyme Modulation at the Blood Brain Barrier

Fridman,

Knerler,

Price

et al. 2023

Preprint

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Background: Appropriate interactions between antiretroviral therapies (ART) and drug transporters and metabolizing enzymes at the blood brain barrier (BBB) are critical to ensure adequate dosing of the brain to achieve HIV suppression. These proteins are modulated by demographic and lifestyle factors, including substance use. While understudied, illicit substances share drug transport and metabolism pathways with ART, increasing the potential for adverse drug-drug interactions. This is particularly important when considering the brain as it is relatively undertreated compared to peripheral organs and is vulnerable to substance use-mediated damage. Methods: We used an in vitro model of the human BBB to determine the extravasation of three first-line ART drugs, emtricitabine (FTC), tenofovir (TFV), and dolutegravir (DTG), in the presence and absence of cocaine, which served as our illicit substance model. The impact of cocaine on BBB integrity and permeability, drug transporters, metabolizing enzymes, and their master transcriptional regulators were evaluated to determine the mechanisms by which substance use impacted ART central nervous system (CNS) availability. Results: We determined that cocaine had a selective impact on ART extravasation, where it increased FTCs ability to cross the BBB while decreasing TFV. DTG concentrations that passed the BBB were below quantifiable limits. Interestingly, the potent neuroinflammatory modulator, lipopolysaccharide, had no effect on ART transport, suggesting a specificity for cocaine. Unexpectedly, cocaine did not breach the BBB, as permeability to albumin and tight junction proteins and adhesion molecules remained unchanged. Rather, cocaine selectively decreased the pregnane-x receptor (PXR), but not constitutive androstane receptor (CAR). Consequently, drug transporter expression and activity decreased in endothelial cells of the BBB, including p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 4 (MRP4). Further, cytochrome P450 3A4 (CYP3A4) enzymatic activity increased following cocaine treatment that coincided with decreased expression. Finally, cocaine modulated adenylate kinases are required to facilitate biotransformation of ART prodrugs to their phosphorylated, pharmacologically active counterparts. Conclusion: Our findings indicate that additional considerations are needed in CNS HIV treatment strategies for people who use cocaine, as it may limit ART efficacy through regulation of drug transport and metabolizing pathways at the BBB.

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“…The cytoskeleton and tight junction proteins are prime mediators of endothelial cell function at the heart of the BBB. A comprehensive discussion of the relationship between various drugs of abuse and cytoskeleton-mediated BBB dysfunction is beyond the scope of this review and we point readers to some recent reviews on this topic [ 127 , 129 , 130 ]. Here we briefly discuss some studies investigating the impact of methamphetamine on brain endothelial cytoskeleton and BBB integrity.…”

Section: Tablementioning

confidence: 99%

IUPHAR-review: Targeting the cytoskeleton as a therapeutic approach to substance use disorders

Pandey,

Miller

2024

Pharmacological Research

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Overview of blood-brain barrier dysfunction in methamphetamine abuse

Cited by 11 publications

References 96 publications

Mesenchymal stem cell‐derived exosomes improve neurogenesis and cognitive function of mice with methamphetamine addiction: A novel treatment approach

Mesenchymal stem cell‐derived exosomes improve neurogenesis and cognitive function of mice with methamphetamine addiction: A novel treatment approach

Cocaine Regulates Antiretroviral Therapy CNS Access Through Pregnane-X Receptor-Mediated Drug Transporter and Metabolizing Enzyme Modulation at the Blood Brain Barrier

IUPHAR-review: Targeting the cytoskeleton as a therapeutic approach to substance use disorders

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