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Aquaporin-4 as a New Target against Methamphetamine-Induced Brain Alterations: Focus on the Neurogliovascular Unit and Motivational Behavior

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Abstract

Methamphetamine (METH) abuse/misuse is a worldwide problem, and despite extensive characterization of its neurotoxicity over the last years, many questions remain unanswered. Recently, it was shown that METH compromises the blood-brain barrier (BBB) and causes a disturbance in the water homeostasis leading to brain edema. Importantly, water transport at BBB is regulated by water channels, aquaporins (AQPs), with AQP4 being expressed in astrocytic end-feet surrounding brain endothelium. Thus, the main goal of this work was to unravel the role of AQP4 under conditions of METH consumption. Our results show that METH (4× 10 mg/kg, 2 h apart, i.p.) interferes with AQP4 protein levels causing brain edema and BBB breakdown in both mice striatum and hippocampus, which culminated in locomotor and motivational impairment. Furthermore, these effects were prevented by pharmacological blockade of AQP4 with a specific inhibitor (TGN-020). Moreover, siRNA knockdown of this water channel protected astrocytes from METH-induced swelling and morphologic alterations. Herein, we unraveled AQP4 as a new therapeutic target to prevent the negative impact of METH.

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Abbreviations

ADC:

Apparent diffusion coefficient

AQP4:

Aquaporin-4

BBB:

Blood-brain barrier

GFAP:

Glial fibrillary acidic protein

METH:

Methamphetamine

MRI:

Magnetic resonance imaging

siRNA:

Small-interfering ribonucleic acid

TGN:

2-(Nicotinamide)-1,3,4-thiadiazole

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Acknowledgements

This work was supported by Project PTDC/SAU-FCF/098685/2008 from Foundation for Science and Technology (FCT Portugal) co-financed by COMPETE and FEDER funds, Pest-C/SAU/UI3282/2013-2014, CNC.IBILI PEst-UID/NEU/04539/2013 and FEDER-COMPETE (FCOMP-01-0124-FEDER-028417 and POCI-01-0145-FEDER-007440). Also, Ph.D. fellowships SFRH/BD/84408/2012 and SFRH/BD/85556/2012 from FCT Portugal co-financed by QREN and POPH/FSE.

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Authors and Affiliations

  1. Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Subunit 1 – Polo 3, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal

    Ricardo Alexandre Leitão, Vanessa Coelho-Santos, Carlos Fontes-Ribeiro & Ana Paula Silva

  2. CNC.IBILI, University of Coimbra, Coimbra, Portugal

    Ricardo Alexandre Leitão, José Sereno, João Miguel Castelhano, Sónia Isabel Gonçalves, Vanessa Coelho-Santos, Carlos Fontes-Ribeiro, Miguel Castelo-Branco & Ana Paula Silva

  3. Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal

    José Sereno, João Miguel Castelhano, Sónia Isabel Gonçalves & Miguel Castelo-Branco

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Fig. S1

METH and AQP4 knockdown does not cause astrocyte cell death. Cells were treated during 24 h with METH (250 μM) and/or TGN (25 μM), non-specific siRNA (Neg siRNA, 20 nM), AQP4 targeting siRNA (siRNA, 20 nM). Results are expressed as mean + S.E.M., n = 4. (GIF 5 kb)

High Resolution Image (TIFF 111 kb)

Fig. S2

Pharmacological inhibition and knockdown of AQP4 cause a downregulation of its protein levels. Primary cultures of mouse cortical astrocytes were exposed to TGN (25 μM for 24 h) or AQP4 targeting siRNA (20 nM for 4 days, siRNA). After the appropriate treatments, we observed a significant decrease in AQP4 (a) protein levels, by western blot analysis, and (b) immunoreactivity. Results are expressed as mean + S.E.M., n = 4 for western blot, and n = 15 for immunocytochemistry. *P < 0.05, **P < 0.01, ***P < 0.001 significantly different when compared to the control (CTR) using one-way ANOVA followed by Dunnet’s Multiple comparison test (GIF 9 kb)

High Resolution Image (TIFF 213 kb)

Fig. S3

METH does not interfere with GFAP protein levels. No significant alterations were observed regarding the GFAP protein levels at 24 h after the different treatments, as follows: 25 μM TGN, 20 nM AQP4 targeting siRNA (siRNA), 250 μM METH. Results are expressed as mean + S.E.M., n = 4. (GIF 9 kb)

High Resolution Image (TIFF 224 kb)

Fig. S4

AQP4 inhibition or knockdown does not cause astrocytic morphological alterations. After the appropriate treatments [TGN (25 μM for 24 h) or AQP4 targeting siRNA (20 nM for 4 days, siRNA)] we did not observe any alterations in astrocytes processes (a) total number or in (b) total length. Results are expressed as mean + S.E.M., n = 15. (GIF 8 kb)

High Resolution Image (TIFF 185 kb)

Fig. S5

Both AQP4 inhibition and silencing decrease cell volume. AQP4 inhibition, by using TGN (25 μM for 24h) or AQP4 knockdown siRNA (20 nM for 4 days, siRNA) silencing methodology, caused a significant reduction in astrocyte cell volume. On the other hand, the Neg siRNA (20 nM non-specific siRNA) did not interfere with the cell size. Results are expressed as mean + S.E.M., n=10. *P<0.05, ***P<0.001 significantly different when compared to the control using one-way ANOVA followed by Dunnet’s Multiple comparison test. (GIF 15.9)

High Resolution Image (TIFF 154 kb)

Fig. S6

Both TGN and VitC are able to prevent the increase of reactive oxygen species triggered by oxygen peroxide. Primary cultures of astrocytes were treated with 500 μM oxygen peroxide (H2O2) for 4 h alone or together with TGN (25 μM) or vitamin C (200 μM; VitC). Here we show that TGN palys a similar role than the well-known antioxidant VitC. Results are expressed as mean % of control + S.E.M., n = 10. **P < 0.01, ***P < 0.001, significantly different when compared to the control (CTR); ### P < 0.001 significantly different when compared to METH using one-way ANOVA followed by Bonferroni’s Multiple comparison test. (GIF 5 kb)

High Resolution Image (TIFF 367 kb)

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Leitão, R.A., Sereno, J., Castelhano, J.M. et al. Aquaporin-4 as a New Target against Methamphetamine-Induced Brain Alterations: Focus on the Neurogliovascular Unit and Motivational Behavior. Mol Neurobiol 55, 2056–2069 (2018). https://doi.org/10.1007/s12035-017-0439-0

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