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. 2020 Nov 20;12(24):25487-25504.
doi: 10.18632/aging.104155. Epub 2020 Nov 20.

Pentoxifylline enhances antioxidative capability and promotes mitochondrial biogenesis for improving age-related behavioral deficits

Yu Wang  1 , Yunxiao Kang  1 , Chunxiao Qi  2 , Tianyun Zhang  1 , Hui Zhao  1 , Xiaoming Ji  1 , Wensheng Yan  3 , Yuanxiang Huang  1 , Rui Cui  2 , Guoliang Zhang  1   2 , Geming Shi  1   4   5
Affiliations

Pentoxifylline enhances antioxidative capability and promotes mitochondrial biogenesis for improving age-related behavioral deficits

Yu Wang et al. Aging (Albany NY). .

Abstract

Pentoxifylline (PTX) is a non-specific phosphodiesterase inhibitor with pleiotropic effects that is routinely used to treat peripheral vascular disease. In this study, we tested whether PTX could also counteract the detrimental effects of aging in the brain. To accomplish that, we treated aged rats with PTX and measured resulting behavioral alterations as well as changes in dopaminergic neurochemical levels, oxidative balance markers, mitochondrial function, nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator activated receptor-gamma coactivator 1-alpha (PGC-1α) and downstream gene expression, and cyclic adenosine monophosphate (cAMP) content in the brain. The results demonstrated that PTX improved motor and cognitive deficits and restored levels of dopamine and its metabolites in the brains of aged rats. PTX also reduced malondialdehyde levels and increased the GSH/GSSG ratio, mitochondrial ATP, nuclear Nrf2, and cAMP levels, and upregulated PGC-1α, nuclear respiratory factor 1, and mitochondrial transcription factor A expression in the substantia nigra and hippocampus of aged rats. Thus, increased nuclear Nrf2 levels and upregulation of PGC-1α, which enhance antioxidative capability and promote mitochondrial biogenesis, may be responsible for PTX-induced amelioration of behavioral deficits in aged rats.

Keywords: aged rats; antioxidative capability; mitochondrial biogenesis; pentoxifylline.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Effects of PTX treatment on motor behavior deficits in aged rats. (A) Effects of PTX treatment on vertical activity. (B) Effects of PTX treatment on horizontal activity. (C) Effects of PTX treatment on total path length. Data are expressed as the mean ± S.D. (n=6 rats/group). *P<0.05 versus 6Mon rats, **P<0.01 versus 6Mon rats, #P<0.05 versus 24Mon rats, ##P<0.01 versus 24Mon rats.
Figure 2
Figure 2
Effects of PTX treatment on cognitive function in aged rats. (A) Effects of PTX treatment on the escape latency of aged rats. (B) Effects of PTX treatment on the number of platform crossings. (C) Effects of PTX treatment on time spent in the target quadrant. Data are expressed as the mean ± S.D. (n=6 rats/group). *P<0.05 versus 6Mon rats, **P<0.01 versus 6Mon rats, #P<0.05 versus 24Mon rats, ##P<0.01 versus 24Mon rats.
Figure 3
Figure 3
Effects of PTX treatment on dopamine and its metabolites in the aged rat brain. (A–C) Effects of PTX treatment on DA, DOPAC, and HVA in the CPu of aged rats. (D–F) Effects of PTX treatment on DA, DOPAC, and HVA in the HIPP of aged rats. Data are expressed as the mean ± S.D. (n=6 rats/group). *P<0.01 versus 6Mon rats, #P<0.05 versus 24Mon rats, ##P<0.01 versus 24Mon rats.
Figure 4
Figure 4
Effects of PTX treatment on brain oxidative balance in aged rats. (A, B) Effects of PTX treatment on MDA levels in the SN and HIPP of aged rats. (C, D) Effects of PTX treatment on GSH/GSSG ratio in the SN and HIPP of aged rats. Data are expressed as the mean ± S.D. (n=6 rats/group). *P<0.05 versus 6Mon rats, **P<0.01 versus 6Mon rats, #P<0.01 versus 24Mon rats.
Figure 5
Figure 5
Effects of PTX treatment on brain mitochondrial ATP levels and complex activity in aged rats. (A) ATP levels in the SN. (B) ATP levels in the HIPP. (C) Mitochondrial complex I activity in the SN. (D, E) Mitochondrial complex V activity in the SN and HIPP. Data are expressed as the mean ± S.D. (n=6 rats/group). *P<0.05, **P<0.01.
Figure 6
Figure 6
Effects of PTX treatment on Nrf2 expression in the aged rat brain. (A, B) Nrf2 mRNA levels in the SN and HIPP were calculated using the 2-ΔΔCt method. GAPDH was used as an internal control. (C, D) Representative Western blots of Nrf2 protein levels in the SN and HIPP. (E, F) Nrf2 protein levels in the SN and HIPP were quantified relative to H3 band density. Data are expressed as the mean ± S.D. (n=6 rats/group). *P<0.01.
Figure 7
Figure 7
Effects of PTX treatment on mitochondrial biogenesis in the SN in aged rats. (A–C) PGC-1α, NRF-1, and TFAM mRNA levels were detected by qPCR. (D–F) Representative Western blots of PGC-1α, NRF-1, and TFAM protein levels. (G–I) PGC-1α, NRF-1, and TFAM protein levels were quantified relative to β-actin band density. Data are expressed as the mean ± S.D. (n=6 rats/group). *P<0.05, **P<0.01.
Figure 8
Figure 8
Effects of PTX treatment on mitochondrial biogenesis in the HIPP in aged rats. (A–C) PGC-1α, NRF-1, and TFAM mRNA levels were detected by qPCR. (D–F) Representative Western blots of PGC-1α, NRF-1, and TFAM protein levels. (G–I) PGC-1α, NRF-1, and TFAM protein levels were quantified relative to β-actin band density. Data are expressed as the mean ± S.D. (n=6 rats/group). *P<0.05, **P<0.01.
Figure 9
Figure 9
Effects of PTX treatment on mitochondrial content in the aged rat brain. (A, B) CS activity in the SN and HIPP. (C, D) mtDNA copy number in the SN and HIPP. (E, F) ATP6 mRNA levels in the SN and HIPP. Data are expressed as the mean ± S.D. (n=6 rats/group). *P<0.05, **P<0.01.
Figure 10
Figure 10
Effects of PTX treatment on cAMP content in the aged rat brain. (A) cAMP content in the SN. (B) cAMP content in the HIPP. Data are expressed as the mean ± S.D. (n=6 rats/group). *P<0.05, **P<0.01.
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