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. 2018 Oct 29:17:999-1017.
doi: 10.17179/excli2018-1626. eCollection 2018.

Everolimus, a mammalian target of rapamycin inhibitor, ameliorated streptozotocin-induced learning and memory deficits via neurochemical alterations in male rats

Sahar Fanoudi  1   2 , Mahmoud Hosseini  3 , Mohaddeseh Sadat Alavi  1   2 , Mohammad Taher Boroushaki  1   2 , Azar Hosseini  2 , Hamid R Sadeghnia  1   2   3
Affiliations

Everolimus, a mammalian target of rapamycin inhibitor, ameliorated streptozotocin-induced learning and memory deficits via neurochemical alterations in male rats

Sahar Fanoudi et al. EXCLI J. .

Abstract

Everolimus (EVR), as a rapamycin analog, is a selective inhibitor of the mammalian target of rapamycin (mTOR) kinase and its associated signaling pathway. mTOR is a serine/threonine protein kinase and its hyperactivity is involved in the pathophysiology of Alzheimer's disease (AD) and associated cognitive deficits. The present study evaluated the impact of EVR, on cognitive functions, hippocampal cell loss, and neurochemical parameters in the intracerebroventricular streptozotocin (icv-STZ) model of AD rats. EVR (1 and 5 mg/kg) was administered for 21 days following the single administration of STZ (3 mg/kg, icv) or for 7 days on days 21-28 post-STZ injection after establishment of cognitive dysfunction. Cognitive deficits (passive avoidance and spatial memory), oxidative stress parameters, acetylcholinesterase (AChE) activity, and percentage of cell loss were evaluated in the hippocampus. Chronic administration (1 and 5 mg/kg for 21 days from the day of surgery and icv-STZ infusion) or acute injection (5 mg/kg for 7 days after establishment of cognitive impairment) of EVR significantly attenuated cognitive dysfunction, neuronal loss, oxidative stress and AChE activity in the hippocampus of STZ-AD rats. In conclusion, our study showed that EVR could prevent or improve deteriorations in behavioral, biochemical and histopathological features of the icv-STZ rat model of AD. Therefore, inhibition of the hyperactivated mTOR may be an important therapeutic target for AD.

Keywords: Alzheimer's disease (AD); acetylcholinesterase; everolimus; mTOR; oxidative stress; streptozotocin.

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Figures

Figure 1
Figure 1. Diagrammatic sketch for the behavioral, biochemical and histopathological experiments. EVR: everolimus; icv-STZ: intracerebroventricular-streptozotocin; PA: passive avoidance; MWM: Morris water maze; SAC: sacrificed for biochemical or histopathological experiments. Day 0 refers to the day of surgery (icv-STZ infusion).
Figure 2
Figure 2. Effects of 7 days (A, on days 21-28 post-STZ infusion, after establishment of cognitive dysfunctions) or 21 days (B, from day 0 which refers to the day of surgery and icv-STZ infusion) administration of EVR on passive avoidance memory of STZ-induced AD rats. The latency to enter the dark chamber of the shuttle box apparatus was acquised before, 3 h and 24 h after delivering electrical foot shock (1 mA, 2 s duration). Values are means ± SEM. ***p < 0.001 vs. STZ group.
Figure 3
Figure 3. Effects of 7 days (A, on days 21-28 post-STZ infusion, after establishment of cognitive dysfunction) or 21 days (B, from day 0 which refers to the day of surgery and icv-STZ infusion) administration of EVR on escape latency of STZ-induced AD rats in Morris water maze (MWM) task. Values are means ± SEM. **p<0.01 and ***p<0.001 vs. STZ group.
Figure 4
Figure 4. Effects of 7 days (A, on days 21-28 post-STZ infusion, after establishment of cognitive dysfunction) or 21 days (B, from day 0 which refers to the day of surgery and icv-STZ infusion) administration of EVR on time spent in target quadrant of STZ-induced AD rats in Morris water maze (MWM) task. Values are means ± SEM. ***p < 0.001 vs. STZ group.
Figure 5
Figure 5. Effects of 7 days (A, on days 21-28 post-STZ infusion, after establishment of cognitive dysfunction) or 21 days (B, from day 0 which refers to the day of surgery and icv-STZ infusion) administration of EVR on swimming speed of STZ-induced AD rats in Morris water maze (MWM) task. Values are means ± SEM. No significant differences were seen between sham-, STZ and EVR-treated rats.
Figure 6
Figure 6. Effects of 7 days (A, on days 21-28 post-STZ infusion, after establishment of cognitive dysfunction) or 21 days (B, from day 0 which refers to the day of surgery and icv-STZ infusion) administration of EVR on malondialdehyde (MDA) level in the hippocampus of STZ-induced AD rats. Values are means ± SEM. *p<0.05, **p<0.01 and ***p < 0.001 vs. STZ group.
Figure 7
Figure 7. Effects of 7 days (A, on days 21-28 post-STZ infusion, after establishment of cognitive dysfunction) or 21 days (B, from day 0 which refers to the day of surgery and icv-STZ infusion) administration of EVR on total thiol level in the hippocampus of STZ-induced AD rats. Values are means ± SEM. *p<0.05, **p < 0.01 and ***p < 0.001 vs. STZ group.
Figure 8
Figure 8. Effects of 7 days (A, on days 21-28 post-STZ infusion, after establishment of cognitive dysfunction) or 21 days (B, from day 0 which refers to the day of surgery and icv-STZ infusion) administration of EVR on acetylcholinesterase (AChE) activity in the hippocampus of STZ-induced AD rats. Values are means ± SEM. **p < 0.01, ***p < 0.001 vs. STZ group.
Figure 9
Figure 9. Effects of 7 days (on days 21-28 post-STZ infusion, after establishment of cognitive dysfunction) or 21 days (from day 0 which refers to the day of surgery and icv-STZ infusion) administration of EVR on cell density of degenerated cells in the hippocampal CA1 region of STZ-induced AD rats.
Figure 10
Figure 10. Effects of 7 days or 21 days administration of EVR on percentage of degenerated cells in the hippocampal CA1 region of STZ-induced AD rats
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