TY - JOUR

T1 - Chronic administration of 7,8-dhf lessens the depression-like behavior of juvenile mild traumatic brain injury treated rats at their adult age

AU - Yang, Shih Te

AU - Hung, Hsiu Yi

AU - Ro, Long Sun

AU - Liao, Ming Feng

AU - Amstislavskaya, Tamara G.

AU - Tikhonova, Maria A.

AU - Yang, Yi Ling

AU - Lu, Kwok Tung

N1 - Funding Information: Acknowledgments: KTL and YLY gratefully acknowledges the financial assistant by MOST, Taiwan, MOST 108-2320-B-003-006-MY3, MOST 107-2320-B-415-006, respectively. This study also partially supported by Russian Science Foundation (grant No. 20-65-46006; supported Y.-L.Y. and T.G.A.; covered the article publication fee and purchase of some reagents, antibodies, and disposals). Funding Information: Funding: The study was funded by Ministry of Science and Technology (MOST), Taiwan, MOST 108-2320-B-003-006-MY3 (KTL); and MOST 107-2320-B-415-006 (YLY). YLY and TGA are also supported by Russian Science Foundation: RSF 20-65-46006. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/12

Y1 - 2021/12

N2 - Traumatic brain injury (TBI) is a leading cause of mortality and morbidity among the global youth and commonly results in long-lasting sequelae, including paralysis, epilepsy, and a host of mental disorders such as major depressive disorder. Previous studies were mainly focused on severe TBI as it occurs in adults. This study explored the long-term adverse effect of mild TBI in juvenile animals (mTBI-J). Male Sprague Dawley rats received mTBI-J or sham treatment at six weeks old, then underwent behavioral, biochemical, and histological experiments three weeks later (at nine weeks old). TTC staining, H&E staining, and brain edema measurement were applied to evaluate the mTBI-J induced cerebral damage. The forced swimming test (FST) and sucrose preference test (SPT) were applied for measuring depression-like behavior. The locomotor activity test (LAT) was performed to examine mTBI-J treatment effects on motor function. After the behavioral experiments, the dorsal hippocampus (dHip) and ventral hippocampus (vHip) were dissected out for western blotting to examine the expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB). Finally, a TrkB agonist 7,8-DHF was injected intraperitoneally to evaluate its therapeutic effect on the mTBI-J induced behavioral abnormalities at the early adult age. Results showed that a mild brain edema occurred, but no significant neural damage was found in the mTBI-J treated animals. In addition, a significant increase of depression-like behaviors was observed in the mTBI-J treated animals; the FST revealed an increase in immobility, and a decrease in sucrose consumption was found in the mTBI-J treated animals. There were no differences observed in the total distance traveled of the LAT and the fall latency of the rotarod test. The hippocampal BDNF expression, but not the TrkB, were significantly reduced in mTBI-J, and the mTBI-J treatment-induced depression-like behavior was lessened after four weeks of 7,8-DHF administration. Collectively, these results indicate that even a mild juvenile TBI treatment that did not produce motor deficits or significant histological damage could have a long-term adverse effect that could be sustained to adulthood, which raises the depression-like behavior in the adult age. In addition, chronic administration of 7,8-DHF lessens the mTBI-J treatment-induced depression-like behaviors in adult rats. We suggest the potential usage of 7,8-DHF as a therapeutic agent for preventing the long-term adverse effect of mTBI-J.

AB - Traumatic brain injury (TBI) is a leading cause of mortality and morbidity among the global youth and commonly results in long-lasting sequelae, including paralysis, epilepsy, and a host of mental disorders such as major depressive disorder. Previous studies were mainly focused on severe TBI as it occurs in adults. This study explored the long-term adverse effect of mild TBI in juvenile animals (mTBI-J). Male Sprague Dawley rats received mTBI-J or sham treatment at six weeks old, then underwent behavioral, biochemical, and histological experiments three weeks later (at nine weeks old). TTC staining, H&E staining, and brain edema measurement were applied to evaluate the mTBI-J induced cerebral damage. The forced swimming test (FST) and sucrose preference test (SPT) were applied for measuring depression-like behavior. The locomotor activity test (LAT) was performed to examine mTBI-J treatment effects on motor function. After the behavioral experiments, the dorsal hippocampus (dHip) and ventral hippocampus (vHip) were dissected out for western blotting to examine the expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB). Finally, a TrkB agonist 7,8-DHF was injected intraperitoneally to evaluate its therapeutic effect on the mTBI-J induced behavioral abnormalities at the early adult age. Results showed that a mild brain edema occurred, but no significant neural damage was found in the mTBI-J treated animals. In addition, a significant increase of depression-like behaviors was observed in the mTBI-J treated animals; the FST revealed an increase in immobility, and a decrease in sucrose consumption was found in the mTBI-J treated animals. There were no differences observed in the total distance traveled of the LAT and the fall latency of the rotarod test. The hippocampal BDNF expression, but not the TrkB, were significantly reduced in mTBI-J, and the mTBI-J treatment-induced depression-like behavior was lessened after four weeks of 7,8-DHF administration. Collectively, these results indicate that even a mild juvenile TBI treatment that did not produce motor deficits or significant histological damage could have a long-term adverse effect that could be sustained to adulthood, which raises the depression-like behavior in the adult age. In addition, chronic administration of 7,8-DHF lessens the mTBI-J treatment-induced depression-like behaviors in adult rats. We suggest the potential usage of 7,8-DHF as a therapeutic agent for preventing the long-term adverse effect of mTBI-J.

KW - Depression-like behavior

KW - Dorsal hippocampus

KW - Juvenile

KW - Mild traumatic brain injury

KW - Ventral hippocampus

UR - http://www.scopus.com/inward/record.url?scp=85121453873&partnerID=8YFLogxK

U2 - 10.3390/pharmaceutics13122169

DO - 10.3390/pharmaceutics13122169

M3 - Article

C2 - 34959450

AN - SCOPUS:85121453873

VL - 13

JO - Pharmaceutics

JF - Pharmaceutics

SN - 1999-4923

IS - 12

M1 - 2169

ER -