Anat Cell Biol.  2024 Mar;57(1):70-84. 10.5115/acb.23.193.

Exploring amygdala structural changes and signaling pathways in postmortem brains: consequences of long-term methamphetamine addiction

• Azimzadeh Z
• Omidvari S
• Niknazar S
• Vafaei-Nezhad S
• Roozbahany NA
• Abdollahifar MA
• Tahmasebinia F
• Mahmoudiasl GR
• Abbaszadeh HA
• Darabi S

• KMID: 2554242
• DOI: http://doi.org/10.5115/acb.23.193

Abstract

Methamphetamine (METH) can potentially disrupt neurotransmitters activities in the central nervous system (CNS) and cause neurotoxicity through various pathways. These pathways include increased production of reactive nitrogen and oxygen species, hypothermia, and induction of mitochondrial apoptosis. In this study, we investigated the long-term effects of METH addiction on the structural changes in the amygdala of postmortem human brains and the involvement of the brain- cAMP response element-binding protein/brain-derived neurotrophic factor (CREB/BDNF) and Akt-1/GSK3 signaling pathways. We examined ten male postmortem brains, comparing control subjects with chronic METH users, using immunohistochemistry, real-time polymerase chain reaction (to measure levels of CREB, BDNF, Akt-1, GSK3, and tumor necrosis factor-α [TNF-α]), Tunnel assay, stereology, and assays for reactive oxygen species (ROS), glutathione disulfide (GSSG), and glutathione peroxidase (GPX). The findings revealed that METH significantly reduced the expression of BDNF, CREB, Akt-1, and GPX while increasing the levels of GSSG, ROS, RIPK3, GSK3, and TNF-α. Furthermore, METH-induced inflammation and neurodegeneration in the amygdala, with ROS production mediated by the CREB/BDNF and Akt-1/GSK3 signaling pathways.

Keyword

Methamphetamine; Brain-derived neurotrophic factor; cAMP response element-binding protein; Amygdala

Figure

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  Fig. 1 Relative quantitative expression levels of key genes in METH and control groups. This figure illustrates the relative quantitative expression levels of critical genes, including CREB, BDNF, Akt-1, GSK3, TNF-α, RIPK3, Caspase 3, Bax, Bcl2, LC3, and ATG5. The outcomes highlight the substantial impact of METH on gene expression, resulting in noteworthy variations involving both upregulation and downregulation of target genes (*P<0.05). METH, methamphetamine; CREB, cAMP response element-binding protein; BDNF, brain-derived neurotrophic factor; TNF-α, tumor necrosis factor-α.

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  Fig. 2 Expression of CREB in control and METH groups. This figure portrays the distinctive expression patterns of CREB in the control (upper row) and the METH group (lower row). The images showcase the cellular nuclei staining using DAPI (Abcam) (A, D), the CREB immunostaining (B, E), and the merged images (C, F). The results effectively demonstrate the significant reduction in CREB expression due to METH exposure within the METH group, with these changes holding substantial significance (***P<0.001). CREB, cAMP response element-binding protein; METH, methamphetamine.

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  Fig. 3 Expression of BDNF in control and METH groups. This figure presents the expression profiles of BDNF in the control (upper row) and the METH group (lower row). The images encompass the nuclei staining using DAPI (Abcam) (A, D), the BDNF immunostaining (B, E), and the merged images (C, F). The findings decisively reveal the METH-induced reduction in BDNF expression within the METH group when compared to the control group (***P<0.001). BDNF, brain-derived neurotrophic factor; METH, methamphetamine.

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  Fig. 4 Akt-1 expression in control and METH groups. This figure assesses the expression of Akt-1 in both the control (upper row) and METH groups (lower row). The panel displays DAPI (Abcam) staining (A, D), Akt-1 immunostaining (B, E), and the merged images (C, F). The findings distinctly reveal that METH administration led to a reduction in Akt-1 expression within the METH group, as compared to the control group, and these alterations held substantial significance (***P<0.001). METH, methamphetamine.

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  Fig. 5 GSK3 expression in METH and control groups depicted here is the expression status of GSK3 in the control group (upper row) and the METH group (lower row). The images feature DAPI (Abcam) staining (A, D), GSK3 immunostaining (B, E), and the merged images (C, F). The results distinctly indicate that METH exposure prompted an elevation in GSK3 expression within the METH group as opposed to the control group, and these changes carried considerable significance (***P<0.001). METH, methamphetamine.

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  Fig. 6 RIPK3 expression in control and METH groups illustrated are the expression profiles of RIPK3 in the control (upper row) and the METH group (lower row). The images present DAPI (Abcam) staining (A, D), RIPK3 immunostaining (B, E), and the merged images (C, F). The outcomes unequivocally highlight that METH exposure resulted in an increased protein expression of RIPK3 within the METH group compared to the control group, and these changes were highly significant (***P<0.001). METH, methamphetamine.

• 

  Fig. 7 TNF-α expression in METH and control groups shown in this figure is the TNF-α expression in the control group (upper row) and the METH group (lower row). The images include DAPI (Abcam) staining (A, D), TNF-α Immunostaining (B, E), and the merged images (C, F). The outcomes vividly showcase that METH exposure induced an augmentation in TNF-α expression within the METH group when compared to the control group, and these alterations held remarkable significance (***P<0.001). TNF-α, tumor necrosis factor-α; METH, methamphetamine.

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  Fig. 8 TUNEL assay results in METH and control groups this figure presents the outcomes of the TUNEL assay within the control group (upper row) and the METH group (lower row). The images encompass DAPI (Abcam) staining (A, D), identification of apoptotic cells (B, E), and the merged images (C, F). The ensuing data substantiates that the presence of apoptotic cells in the METH group demonstrated a substantial increase as contrasted with the control group (***P<0.001). METH, methamphetamine.

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  Fig. 9 The figure showcases the results concerning GPX activation, GSSG activity, and ROS levels in both the METH and control groups. It elucidates that METH exposure led to heightened ROS and GSSG activity, while concurrently decreasing GPX activity in comparison with the control group (***P<0.001). DFC, dichlorodihydrofluorescein; GPX, glutathione peroxidase; GSSG, glutathione disulfide; ROS, reactive oxygen species; METH, methamphetamine.

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  Fig. 10 (A) Photomicrograph and (B) stereological data of neurons and glial cells in control and METH groups. Panel (A) provides a visual representation of the amygdala nuclei stained with H&E and cresyl violet, accentuating the pronounced neuronal vacuolation and gliosis in the control group (upper row) in comparison with METH group (lower row), the panel (B) encompasses stereological data indicating the quantification of neurons and glial cells in both the control and METH groups. Specifically, the number of neurons displayed a reduction in the METH groups when contrasted with the control group, whereas the number of glial cells exhibited an increase (***P<0.001). N, neuron; G, glial cell; METH, methamphetamine.

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  Fig. 11 Immunoblotting analysis of GSK3, TNF-α, RIPK3, CREB, BDNF, and Akt-1 levels in response to METH. This figure demonstrates the outcomes of immunoblotting assessing the levels of GSK3, TNF-α, and RIPK3, along with CREB, BDNF, and Akt-1, in response to METH exposure. ACTIN is effectively used as the loading control in the blots to ensure data accuracy and reliability (**P<0.01, ***P<0.001, ****P<0.0001). TNF-α, tumor necrosis factor-α; CREB, cAMP response element-binding protein; BDNF, brain-derived neurotrophic factor; METH, methamphetamine.

Reference

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