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. 2022 Sep 19:2022:8902262.
doi: 10.1155/2022/8902262. eCollection 2022.

ZOMEC via the p-Akt/Nrf2 Pathway Restored PTZ-Induced Oxidative Stress-Mediated Memory Dysfunction in Mouse Model

Rifat Jahan  1   2 , Mohammad Yousaf  1 , Hamayun Khan  1 , Nousheen Bibi  3 , Musarrat Ijaz  4 , Touseef Rehan  5 , Shahid Ali Shah  6
Affiliations

ZOMEC via the p-Akt/Nrf2 Pathway Restored PTZ-Induced Oxidative Stress-Mediated Memory Dysfunction in Mouse Model

Rifat Jahan et al. Biomed Res Int. .

Retraction in

Abstract

A new mechanistic approach to overcome the neurodegenerative disorders caused by oxidative stress in Alzheimer's disease (AD) is highly stressed in this article. Thus, a newly formulated drug (zinc ortho-methyl carbonodithioate (ZOMEC)) was investigated for five weeks on seven-week-old BALB/c male mice. ZOMEC 30 mg/kg was postadministered intraperitoneally during the third week of pentylenetetrazole (PTZ) injection. The brain homogenates of the mice were evaluated for their antioxidant potential for ZOMEC. The results including catalase (CAT), glutathione S transferase (GST), and lipid peroxidation (LPO) demonstrated that ZOMEC significantly reverted the oxidative stress stimulated by PTZ in the mouse brain. ZOMEC upregulated p-Akt/Nrf-2 pathways (also supported by molecular docking methods) to revoke PTZ-induced apoptotic protein markers. ZOMEC reversed PTZ-induced neuronal synapse deficits, improved oxidative stress-aided memory impairment, and inhibited the amyloidogenic pathway in mouse brains. The results suggested the potential of ZOMEC as a new, safe, and neurotherapeutic agent to cure neurodegenerative disorders by decreasing AD-like neuropathology in the animal PTZ model.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
ZOMEC reduced PTZ-induced oxidative stress. Shown are the different antioxidant enzyme assays including (a) CAT, (b) GST, and (c) LPO. Significance: ###p ≤ 0.001, ∗∗p ≤ 0.01, @p ≤ 0.05, and ns = no significance.
Figure 2
Figure 2
Activated glial cells (PTZ-induced) were deactivation by our test drug ZOMEC. (a) Shown are the immunoblots of glial cells, Iba-1 and GFAP (both microglia and astrocytes). (b) Histogram of microglia. (c) Histogram of astrocytes. Significance: ##p ≤ 0.01, ∗∗p ≤ 0.01, and ns = no significance.
Figure 3
Figure 3
ZOMEC reduced PTZ-induced neuroapoptosis in adult mice. Shown are the different apoptotic protein markers including (a) immunoblot of BAX, Bcl2, BAX/Bcl2, caspase-3, and PARP-1, while histograms of all the markers are shown as (b) BAX, (c) Bcl2, (d) BAX/Bcl2, (e) caspase-3, and (f) PARP-1. Significance: ###p ≤ 0.001, ##p ≤ 0.01, ∗∗∗p ≤ 0.001, ∗∗p ≤ 0.01, @p ≤ 0.05, @@@p ≤ 0.001, and ns = no significance.
Figure 4
Figure 4
ZOMEC significantly downregulated Aβ accumulation and BASE1 production in mouse brains. Shown are the western blot results of Aβ and BACE1. (a) Immunoblot of Aβ and BACE1. (b) Histogram of Aβ. (c) BACE1. These representative bar graphs show the relative density of proteins in the selected groups. Significance: ###p ≤ 0.001, ∗∗p ≤ 0.01, and ns = no significance.
Figure 5
Figure 5
ZOMEC increased SYP and PSD95 activities in the brain (n = 5 animals/group). (a) Immunoblot of SYP and PSD95. (b) The histogram shows a significant increase of SYP levels in the PTZ+ZOMEC group. (c) Significant increase of PSD95 activity with the administration of ZOMEC. Significance: ##p ≤ 0.01 and ∗∗p ≤ 0.01.
Figure 6
Figure 6
ZOMEC successfully reversed PTZ-induced memory dysfunction in mice (n = 5 animals/group). (a) Given are the results for mean escape latency of the MWM for all four experimental groups for five days. (b) Probe test: performed during MWM on day sixth when the submerged stand was absent. (c) The percent spontaneous alteration of selected mouse groups in Y-maze. Significance: ##p ≤ 0.01, ∗∗∗p ≤ 0.001, ∗∗p ≤ 0.01, @p ≤ 0.05, and ns = no significance.
Figure 7
Figure 7
ZOMEC activated the p-Akt/Nrf-2 signaling pathway to decrease neurodegeneration and memory impairment. (a) Immunoblot results for p-Akt and Nrf-2 protein markers. (b) p-Akt histogram. (c) Nrf-2 histogram. (d) HO-1 histogram. (e) Binding mode and interaction of ZOMEC with p-Akt. (e) A: hydrophobic representation of p-Akt protein with bound ZOMEC shown in zoom view. B: p-Akt protein in ribbon representation with binding residues shown in yellow sticks and ZOMEC in red sticks. (f) Binding mode and interaction of ZOMEC with Nrf2. (f) A: hydrophobic representation of Nrf2 protein with bound ZOMEC shown in zoom view. B: Nrf2 protein in ribbon representation with binding residues shown in blue sticks and ZOMEC in red sticks. Significance: ###p ≤ 0.001, ∗∗∗p ≤ 0.001, ∗∗p ≤ 0.01, @p ≤ 0.05, @@p ≤ 0.01, and ns = no significance.
Figure 8
Figure 8
The schematic representation of the proposed pathway followed by ZOMEC.
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