Inhibition of the Rho/ROCK pathway prevents neuronal degeneration in vitro and in vivo following methylmercury exposure

Journal Article · Sat Jan 01 00:00:00 EST 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.09.011· OSTI ID:21535198

Fujimura, Masatake ^[1]; Usuki, Fusako ^[2]; Kawamura, Miwako; Izumo, Shuji ^[3]

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1. Department of Basic Medical Sciences, National Institute for Minamata Disease, Kumamoto (Japan)
2. Department of Clinical Medicine, National Institute for Minamata Disease, Kumamoto (Japan)
3. Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima (Japan)

Methylmercury (MeHg) is an environmental neurotoxicant which induces neuropathological changes in both the central nervous and peripheral sensory nervous systems. Our recent study demonstrated that down-regulation of Ras-related C3 botulinum toxin substrate 1 (Rac1), which is known to promote neuritic extension, preceded MeHg-induced damage in cultured cortical neurons, suggesting that MeHg-mediated axonal degeneration is due to the disturbance of neuritic extension. Therefore we hypothesized that MeHg-induced axonal degeneration might be caused by neuritic extension/retraction incoordination. This idea brought our attention to the Ras homolog gene (Rho)/Rho-associated coiled coil-forming protein kinase (ROCK) pathway because it has been known to be associated with the development of axon and apoptotic neuronal cell death. Here we show that inhibition of the Rho/ROCK pathway prevents MeHg-intoxication both in vitro and in vivo. A Rho inhibitor, C3 toxin, and 2 ROCK inhibitors, Fasudil and Y-27632, significantly protected against MeHg-induced axonal degeneration and apoptotic neuronal cell death in cultured cortical neuronal cells exposed to 100 nM MeHg for 3 days. Furthermore, Fasudil partially prevented the loss of large pale neurons in dorsal root ganglia, axonal degeneration in dorsal spinal root nerves, and vacuolar degeneration in the dorsal columns of the spinal cord in MeHg-intoxicated model rats (20 ppm MeHg in drinking water for 28 days). Hind limb crossing sign, a characteristic MeHg-intoxicated sign, was significantly suppressed in this model. The results suggest that inhibition of the Rho/ROCK pathway rescues MeHg-mediated neuritic extension/retraction incoordination and is effective for the prevention of MeHg-induced axonal degeneration and apoptotic neuronal cell death.

• OSTI ID: 21535198
• Journal Information: Toxicology and Applied Pharmacology, Vol. 250, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.09.011; PII: S0041-008X(10)00353-4; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
DISTURBANCES
DRINKING WATER
ENZYMES
GENES
IN VITRO
IN VIVO
INHIBITION
LABELLING
METHYLMERCURY
NERVE CELLS
NERVES
RATS
SPINAL CORD
SUBSTRATES
TOXINS
ANIMAL CELLS
ANIMALS
ANTIGENS
CENTRAL NERVOUS SYSTEM
HAZARDOUS MATERIALS
HYDROGEN COMPOUNDS
MAMMALS
MATERIALS
NERVOUS SYSTEM
ORGANIC COMPOUNDS
ORGANIC MERCURY COMPOUNDS
OXYGEN COMPOUNDS
PROTEINS
RODENTS
SOMATIC CELLS
TOXIC MATERIALS
VERTEBRATES
WATER