Evaluation of neurobehavioral impairment in methylmercury‐treated KK‐Ay mice by dynamic weight‐bearing test

Abstract

Methylmercury (MeHg) is known to cause neurobehavioral impairment in human and experimental animals. We previously reported that MeHg (5 mg Hg/kg) induced severe neurobehavioral dysfunction in 4-week-old KK-Ay mice, although it is difficult to evaluate quantitatively the neurobehavioral impairment in MeHg-treated KK-Ay mice because of their obesity. The aim of this study was to evaluate MeHg-induced neurobehavioral dysfunction in KK-Ay mice using the dynamic weight-bearing test, which analyzes the animal's weight distribution between the four limbs. Male 12-week-old KK-Ay mice were treated with MeHg (5 mg Hg/kg) three times per week for 5 weeks. Body weight loss began after approximately 2 weeks of MeHg treatment, and decreased significantly at 4 weeks. Seven of the nine MeHg-treated mice exhibited overt neurological symptoms such as ataxia and gait disturbance. The weight-bearing load was lower for the forelimb than for the hindlimb at baseline and until 1 week after MeHg treatment was initiated. In weeks 2-4, the dynamic weight-bearing loads on the forelimb and hindlimb were similar. The load on the forelimb exceeded the load on the hindlimb after 5 weeks of treatment. This finding indicates that the dynamic weight-bearing test is useful for semi-quantitative evaluation of neurobehavioral impairment in MeHg-treated rodents, and is less stressful for the animals. Infiltration of CD204-positive macrophages was observed in the sciatic nerve of MeHg-treated mice, suggesting that CD204 can serve as a useful marker of tissue injury in peripheral nerves and a possible target in regenerating peripheral nerves and controlling neuropathies.

Inorganic mercury‑induced MIP‑2 expression is suppressed by N‑acetyl‑L‑cysteine in RAW264.7 macrophages

“…Conversely, these cells may hinder tissue damage in the brain (33). Infiltration of CD204-positive macrophages was previously observed in the sciatic nerve of MeHg-treated KK-Ay mice, suggesting that macrophages can also serve an important role in the recovery of injured tissues in peripheral nerves, and as a possible target in regenerating peripheral nerves and controlling neuropathies (4). Future studies to identify the specific role of activated MIP-2 and MCP-5 expression �f��� �x������ �� Hg 2+ , and the effects of NAC in vivo, ��� warranted.…”

“…In the brain of patients with Minamata disease, the accumulation of macrophages was observed around brain lesions, and Hg was detected in neurons, ���������� ����� ��d �����������, ��d������� ��� ��������� involvement of macrophages in MeHg-induced neurotoxicity (2). Furthermore, the infiltration of CD204-positive macrophages in the brains of MeHg-exposed KK-Ay mice has been reported (3,4). Acute and chronic brain inflammation induces brain injury and neurodegenerative disorders (5), and ����������� ��d ��������� ��� ������ ��d������� �f ������ and regeneration in the central nervous system (6).…”

Toxicokinetics of methylmercury in diabetic KK‐Ay mice and C57BL/6 mice

“…MeHg tended to show longer retention in BL/6 mice in this single acute exposure. In our previous chronic administration studies, Hg accumulated in blood and tissues to a greater extent in KK‐Ay mice (Yamamoto et al, 2014; Yamamoto et al, 2019). The chronic high‐dose MeHg exposure used in these studies (5 mg Hg/kg three times per week for several weeks) caused tissue damage, which may explain the dysregulation of MeHg metabolism in KK‐Ay mice.…”

“…Samples were heated to 80°C for 20 min and then homogenized. Total mercury (T‐Hg) in the homogenate was determined with a direct thermal decomposition mercury analyzer (MA‐3000; Nippon Instruments, Tokyo, Japan) as described previously (Yamamoto et al, 2012; Yamamoto et al, 2014; Yamamoto et al, 2019).…”

Carrageenan-Induced Non-Painful Inflammation Reduces Voluntary Sucrose Consumption in a Two-Bottle Choice Paradigm: A New Model of Inflammation Induced Anhedonia

“…Mechanical nociceptive thresholds were evaluated using an automated Von Frey-type dynamic plantar esthesiometer, as described before [22] [23]. Briefly, each rat was placed in a plastic cage with a wire mesh floor.…”