Heatstroke-induced late-onset neurological deficits in mice caused by white matter demyelination, Purkinje cell degeneration, and synaptic impairment in the cerebellum

Abstract

Global warming increases heatstroke incidence. After heatstroke, patients exhibit neurological symptoms, suggesting cerebellar damage. However, the potential long-term adverse outcomes are poorly understood. We studied the cerebellum after heatstroke in mouse heatstroke models. In this study, motor coordination disorder significantly appeared 3 weeks after heatstroke and gradually improved to some extent. Although white matter demyelination was detected at 1 and 3 weeks after heatstroke in the cerebellum, it was not found in the corpus callosum. The Purkinje cell numbers significantly decreased at 1, 3, and 9 weeks after heatstroke. The intensity of synaptophysin and postsynaptic density-95 temporarily appeared to attenuate at 3 weeks after heatstroke; however, both appeared to intensify at 9 weeks after heatstroke. Motor coordination loss occurred a few weeks after heatstroke and recovered to some extent. Late-onset motor impairment was suggested to be caused by cerebellar dysfunctions morphologically assessed by myelin staining of cerebellar white matter and immunostaining of Purkinje cells with pre- and postsynaptic markers. Purkinje cell number did not recover for 9 weeks; other factors, including motor coordination, partially recovered, probably by synaptic reconstruction, residual Purkinje cells, and other cerebellar white matter remyelination. These phenomena were associated with late-onset neurological deficits and recovery after heatstroke.

Effect of PACAP on Heat Exposure

“…We previously reported a heat stroke model in the C57/BL6 strain of mice [ 8 , 9 ], but not in the ICR strain of mice. In our preliminary study, when ICR mice were exposed to heat stress at approximately 41 °C ambient temperatures and >99% relative humidity for 60 min, the same as our previous conditions, these conditions were lethal to ICR mice.…”

“…Moreover, we did not examine the effect of heat dissipation on maintaining thermo-homeostasis in detail. Secondly, we previously reported that heat exposure induces progressive multiple organ failure and cerebellar damage [ 8 , 9 ]. As PACAP is well known to protect various tissues from damage, in the present study, we only examined consequences immediately after heat exposure and did not examine the net effect of PACAP on the tissue damage following heat stress.…”

“…However, in addition to heat, the high humidity of tropical regions including Japan in the summer prevents heat diffusion and vaporing from the body and critically increases the risk of heat stroke. Therefore, we developed an experimental mouse model (C57/BL6 strain) of heat stroke to resemble summer in tropical regions [ 8 , 9 ]. The model showed a biphasic abnormal thermoresponse, abnormal blood parameters, and multiple organ failure [ 8 ].…”

“…The model showed a biphasic abnormal thermoresponse, abnormal blood parameters, and multiple organ failure [ 8 ]. Moreover, the animals exhibited loss of motor coordination and cerebellar cells [ 9 ].…”

Amide proton transfer imaging in rats after heatstroke

“…Heatstroke endangers the life safety of patients, often leading to hyperthermia, neurological disorders, and cognitive impairment [19]. Common sites of injury in heatstroke include the cerebellum [2], hippocampus [20], midbrain, thalamus [21], and cerebral cortex [22,23]. Studies have shown that heatstroke can lead to decreased arterial pressure and insufficient cerebral perfusion, resulting in ischemia and hypoxia and changes in the pH of the brain tissue environment [24].…”