TY - JOUR
T1 - Therapeutic benefits of maintaining mitochondrial integrity and calcium homeostasis by forced expression of Hsp27 in chemotherapy-induced peripheral neuropathy
AU - Chine, Virendra Bhagawan
AU - Au, Ngan Pan Bennett
AU - Ma, Chi Him Eddie
N1 - Funding Information:
This work is supported in part by General Research Fund (GRF) from The Research Grant Council of the Hong Kong Special Administrative Region Government ( CityU 11100015 , CityU 11100417 , and CityU 11100318 ), and The Health and Medical Research Fund (HMRF), Food and Health Bureau, Hong Kong Special Administrative Region Government (Ref. no.: 05160126 ), The Innovation and Technology Fund, Innovation and Technology Commission (Ref. no.: ITS/151/17 ), and The CityU Applied Research Grant, City University of Hong Kong (Ref. no.: 9667149 ) award to Chi Ma.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Background: Vincristine, a widely used antineoplastic agent, is known to be neurotoxic and to lead to chemotherapy-induced peripheral neuropathy (CIPN), which is characterized by nerve damage. Growing evidence suggests that disruption of intracellular calcium homeostasis in peripheral neurons contributes largely to the pathological conditions of CIPN. Our previous study showed that forced expression of a peripheral nerve injury-induced small heat shock protein (Hsp), Hsp27, accelerates axon regeneration and functional recovery. In the current study, we examined whether neuronal expression of human Hsp27 (hHsp27) can prevent the inhibitory effects of vincristine in two mouse models of peripheral nerve injury, namely, sciatic nerve crush and CIPN. Methods: The protective effects of hHsp27 against vincristine were examined in mouse models of both sciatic nerve crush and CIPN using multiple approaches, including animal behavioral tests, histology, electrophysiology, transmission electron microscopy and calcium imaging. Results: Vincristine delayed functional recovery in littermate mice; however, hHsp27 Tg mice were unaffected after vincristine treatment and sciatic nerve crush. In CIPN mice, hHsp27 protected against vincristine-induced mechanical and cold allodynia by preventing axonal degeneration, demyelination, mitochondrial dysfunction, and apoptosis. Strikingly, vincristine-induced calcium influx was markedly attenuated in sensory neurons of hHsp27 Tg mice. Conclusions: Our findings suggest that preserving myelin and mitochondrial integrity as well as maintaining intracellular calcium homeostasis is beneficial for preventing CIPN, and these findings shed new light on the development of anti-CIPN drugs.
AB - Background: Vincristine, a widely used antineoplastic agent, is known to be neurotoxic and to lead to chemotherapy-induced peripheral neuropathy (CIPN), which is characterized by nerve damage. Growing evidence suggests that disruption of intracellular calcium homeostasis in peripheral neurons contributes largely to the pathological conditions of CIPN. Our previous study showed that forced expression of a peripheral nerve injury-induced small heat shock protein (Hsp), Hsp27, accelerates axon regeneration and functional recovery. In the current study, we examined whether neuronal expression of human Hsp27 (hHsp27) can prevent the inhibitory effects of vincristine in two mouse models of peripheral nerve injury, namely, sciatic nerve crush and CIPN. Methods: The protective effects of hHsp27 against vincristine were examined in mouse models of both sciatic nerve crush and CIPN using multiple approaches, including animal behavioral tests, histology, electrophysiology, transmission electron microscopy and calcium imaging. Results: Vincristine delayed functional recovery in littermate mice; however, hHsp27 Tg mice were unaffected after vincristine treatment and sciatic nerve crush. In CIPN mice, hHsp27 protected against vincristine-induced mechanical and cold allodynia by preventing axonal degeneration, demyelination, mitochondrial dysfunction, and apoptosis. Strikingly, vincristine-induced calcium influx was markedly attenuated in sensory neurons of hHsp27 Tg mice. Conclusions: Our findings suggest that preserving myelin and mitochondrial integrity as well as maintaining intracellular calcium homeostasis is beneficial for preventing CIPN, and these findings shed new light on the development of anti-CIPN drugs.
KW - Axon degeneration
KW - Chemotherapy-induced peripheral neuropathy
KW - Demyelination
KW - Heat shock protein 27
KW - Intracellular calcium
KW - Mechanical and cold allodynia
KW - Vincristine
UR - http://www.scopus.com/inward/record.url?scp=85067519099&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2019.104492
DO - 10.1016/j.nbd.2019.104492
M3 - Article
C2 - 31176721
AN - SCOPUS:85067519099
SN - 0969-9961
VL - 130
JO - Neurobiology of Disease
JF - Neurobiology of Disease
M1 - 104492
ER -