Liposomal melatonin rescues methamphetamine-elicited mitochondrial burdens, pro-apoptosis, and dopaminergic degeneration through the inhibition PKCδ gene

Xuan Khanh Thi Nguyen, Jaehwi Lee, Eun Joo Shin, Duy Khanh Dang, Ji Hoon Jeong, Thuy Ty Lan Nguyen, Yunsung Nam, Hyun Jong Cho, Jae Chul Lee, Dae Hun Park, Choon Gon Jang, Jau Shyong Hong, Toshitaka Nabeshima, Hyoung Chun Kim

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

We have demonstrated that mitochondrial oxidative damage and PKCδ overexpression contribute to methamphetamine-induced dopaminergic degeneration. Although it is recognized that antioxidant melatonin is effective in preventing neurotoxicity induced by methamphetamine, its precise mechanism remains elusive. C57BL/6J wild-type mice exhibited a similar degree of dopaminergic deficit when methamphetamine was administered during light and dark phases. Furthermore, dopaminergic neuroprotection by genetic inhibition of PKCδ during the light phase was comparable to that during the dark phase. Thus, we have focused on the light phase to examine whether melatonin modulates PKCδ-mediated neurotoxic signaling after multiple high doses of methamphetamine. To enhance the bioavailability of melatonin, we applied liposomal melatonin. Treatment with methamphetamine resulted in hyperthermia, mitochondrial translocation of PKCδ, oxidative damage (mitochondria > cytosol), mitochondrial dysfunction, pro-apoptotic changes, ultrastructural mitochondrial degeneration, dopaminergic degeneration, and behavioral impairment in wild-type mice. Treatment with liposomal melatonin resulted in a dose-dependent attenuation against degenerative changes induced by methamphetamine in wild-type mice. Attenuation by liposomal melatonin might be comparable to that by genetic inhibition (using PKCδ(-/-) mice or PKCδ antisense oligonucleotide). However, liposomal melatonin did not show any additional protective effects on the attenuation by genetic inhibition of PKCδ. Our results suggest that the circadian cycle cannot be a key factor in modulating methamphetamine toxicity under the current experimental condition and that PKCδ is one of the critical target genes for melatonin-mediated protective effects against mitochondrial burdens (dysfunction), oxidative stress, pro-apoptosis, and dopaminergic degeneration induced by methamphetamine.

Original languageEnglish
Pages (from-to)86-106
Number of pages21
JournalJournal of Pineal Research
Volume58
Issue number1
DOIs
Publication statusPublished - 01-01-2015

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Methamphetamine
Melatonin
Apoptosis
Genes
Light
Antisense Oligonucleotides
Cytosol
Biological Availability
Mitochondria
Oxidative Stress
Fever
Antioxidants

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

Nguyen, Xuan Khanh Thi ; Lee, Jaehwi ; Shin, Eun Joo ; Dang, Duy Khanh ; Jeong, Ji Hoon ; Nguyen, Thuy Ty Lan ; Nam, Yunsung ; Cho, Hyun Jong ; Lee, Jae Chul ; Park, Dae Hun ; Jang, Choon Gon ; Hong, Jau Shyong ; Nabeshima, Toshitaka ; Kim, Hyoung Chun. / Liposomal melatonin rescues methamphetamine-elicited mitochondrial burdens, pro-apoptosis, and dopaminergic degeneration through the inhibition PKCδ gene. In: Journal of Pineal Research. 2015 ; Vol. 58, No. 1. pp. 86-106.
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title = "Liposomal melatonin rescues methamphetamine-elicited mitochondrial burdens, pro-apoptosis, and dopaminergic degeneration through the inhibition PKCδ gene",
abstract = "We have demonstrated that mitochondrial oxidative damage and PKCδ overexpression contribute to methamphetamine-induced dopaminergic degeneration. Although it is recognized that antioxidant melatonin is effective in preventing neurotoxicity induced by methamphetamine, its precise mechanism remains elusive. C57BL/6J wild-type mice exhibited a similar degree of dopaminergic deficit when methamphetamine was administered during light and dark phases. Furthermore, dopaminergic neuroprotection by genetic inhibition of PKCδ during the light phase was comparable to that during the dark phase. Thus, we have focused on the light phase to examine whether melatonin modulates PKCδ-mediated neurotoxic signaling after multiple high doses of methamphetamine. To enhance the bioavailability of melatonin, we applied liposomal melatonin. Treatment with methamphetamine resulted in hyperthermia, mitochondrial translocation of PKCδ, oxidative damage (mitochondria > cytosol), mitochondrial dysfunction, pro-apoptotic changes, ultrastructural mitochondrial degeneration, dopaminergic degeneration, and behavioral impairment in wild-type mice. Treatment with liposomal melatonin resulted in a dose-dependent attenuation against degenerative changes induced by methamphetamine in wild-type mice. Attenuation by liposomal melatonin might be comparable to that by genetic inhibition (using PKCδ(-/-) mice or PKCδ antisense oligonucleotide). However, liposomal melatonin did not show any additional protective effects on the attenuation by genetic inhibition of PKCδ. Our results suggest that the circadian cycle cannot be a key factor in modulating methamphetamine toxicity under the current experimental condition and that PKCδ is one of the critical target genes for melatonin-mediated protective effects against mitochondrial burdens (dysfunction), oxidative stress, pro-apoptosis, and dopaminergic degeneration induced by methamphetamine.",
author = "Nguyen, {Xuan Khanh Thi} and Jaehwi Lee and Shin, {Eun Joo} and Dang, {Duy Khanh} and Jeong, {Ji Hoon} and Nguyen, {Thuy Ty Lan} and Yunsung Nam and Cho, {Hyun Jong} and Lee, {Jae Chul} and Park, {Dae Hun} and Jang, {Choon Gon} and Hong, {Jau Shyong} and Toshitaka Nabeshima and Kim, {Hyoung Chun}",
year = "2015",
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Nguyen, XKT, Lee, J, Shin, EJ, Dang, DK, Jeong, JH, Nguyen, TTL, Nam, Y, Cho, HJ, Lee, JC, Park, DH, Jang, CG, Hong, JS, Nabeshima, T & Kim, HC 2015, 'Liposomal melatonin rescues methamphetamine-elicited mitochondrial burdens, pro-apoptosis, and dopaminergic degeneration through the inhibition PKCδ gene', Journal of Pineal Research, vol. 58, no. 1, pp. 86-106. https://doi.org/10.1111/jpi.12195

Liposomal melatonin rescues methamphetamine-elicited mitochondrial burdens, pro-apoptosis, and dopaminergic degeneration through the inhibition PKCδ gene. / Nguyen, Xuan Khanh Thi; Lee, Jaehwi; Shin, Eun Joo; Dang, Duy Khanh; Jeong, Ji Hoon; Nguyen, Thuy Ty Lan; Nam, Yunsung; Cho, Hyun Jong; Lee, Jae Chul; Park, Dae Hun; Jang, Choon Gon; Hong, Jau Shyong; Nabeshima, Toshitaka; Kim, Hyoung Chun.

In: Journal of Pineal Research, Vol. 58, No. 1, 01.01.2015, p. 86-106.

Research output: Contribution to journalArticle

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T1 - Liposomal melatonin rescues methamphetamine-elicited mitochondrial burdens, pro-apoptosis, and dopaminergic degeneration through the inhibition PKCδ gene

AU - Nguyen, Xuan Khanh Thi

AU - Lee, Jaehwi

AU - Shin, Eun Joo

AU - Dang, Duy Khanh

AU - Jeong, Ji Hoon

AU - Nguyen, Thuy Ty Lan

AU - Nam, Yunsung

AU - Cho, Hyun Jong

AU - Lee, Jae Chul

AU - Park, Dae Hun

AU - Jang, Choon Gon

AU - Hong, Jau Shyong

AU - Nabeshima, Toshitaka

AU - Kim, Hyoung Chun

PY - 2015/1/1

Y1 - 2015/1/1

N2 - We have demonstrated that mitochondrial oxidative damage and PKCδ overexpression contribute to methamphetamine-induced dopaminergic degeneration. Although it is recognized that antioxidant melatonin is effective in preventing neurotoxicity induced by methamphetamine, its precise mechanism remains elusive. C57BL/6J wild-type mice exhibited a similar degree of dopaminergic deficit when methamphetamine was administered during light and dark phases. Furthermore, dopaminergic neuroprotection by genetic inhibition of PKCδ during the light phase was comparable to that during the dark phase. Thus, we have focused on the light phase to examine whether melatonin modulates PKCδ-mediated neurotoxic signaling after multiple high doses of methamphetamine. To enhance the bioavailability of melatonin, we applied liposomal melatonin. Treatment with methamphetamine resulted in hyperthermia, mitochondrial translocation of PKCδ, oxidative damage (mitochondria > cytosol), mitochondrial dysfunction, pro-apoptotic changes, ultrastructural mitochondrial degeneration, dopaminergic degeneration, and behavioral impairment in wild-type mice. Treatment with liposomal melatonin resulted in a dose-dependent attenuation against degenerative changes induced by methamphetamine in wild-type mice. Attenuation by liposomal melatonin might be comparable to that by genetic inhibition (using PKCδ(-/-) mice or PKCδ antisense oligonucleotide). However, liposomal melatonin did not show any additional protective effects on the attenuation by genetic inhibition of PKCδ. Our results suggest that the circadian cycle cannot be a key factor in modulating methamphetamine toxicity under the current experimental condition and that PKCδ is one of the critical target genes for melatonin-mediated protective effects against mitochondrial burdens (dysfunction), oxidative stress, pro-apoptosis, and dopaminergic degeneration induced by methamphetamine.

AB - We have demonstrated that mitochondrial oxidative damage and PKCδ overexpression contribute to methamphetamine-induced dopaminergic degeneration. Although it is recognized that antioxidant melatonin is effective in preventing neurotoxicity induced by methamphetamine, its precise mechanism remains elusive. C57BL/6J wild-type mice exhibited a similar degree of dopaminergic deficit when methamphetamine was administered during light and dark phases. Furthermore, dopaminergic neuroprotection by genetic inhibition of PKCδ during the light phase was comparable to that during the dark phase. Thus, we have focused on the light phase to examine whether melatonin modulates PKCδ-mediated neurotoxic signaling after multiple high doses of methamphetamine. To enhance the bioavailability of melatonin, we applied liposomal melatonin. Treatment with methamphetamine resulted in hyperthermia, mitochondrial translocation of PKCδ, oxidative damage (mitochondria > cytosol), mitochondrial dysfunction, pro-apoptotic changes, ultrastructural mitochondrial degeneration, dopaminergic degeneration, and behavioral impairment in wild-type mice. Treatment with liposomal melatonin resulted in a dose-dependent attenuation against degenerative changes induced by methamphetamine in wild-type mice. Attenuation by liposomal melatonin might be comparable to that by genetic inhibition (using PKCδ(-/-) mice or PKCδ antisense oligonucleotide). However, liposomal melatonin did not show any additional protective effects on the attenuation by genetic inhibition of PKCδ. Our results suggest that the circadian cycle cannot be a key factor in modulating methamphetamine toxicity under the current experimental condition and that PKCδ is one of the critical target genes for melatonin-mediated protective effects against mitochondrial burdens (dysfunction), oxidative stress, pro-apoptosis, and dopaminergic degeneration induced by methamphetamine.

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