Kai-Xin-San Attenuates Doxorubicin-Induced Cognitive Impairment by Reducing Inflammation, Oxidative Stress, and Neural Degeneration in 4T1 Breast Cancer Mice

Objective. This study explored the potential therapeutic effect and possible mechanism of Kai-Xin-San (KXS) on doxorubicin-induced cognitive impairment in 4T1 breast cancer mice. Methods. A model of chemotherapy-induced cognitive impairment (CICI) was established with the injection of doxorubicin (DOX, 5 mg/kg) at a 7-day interval in a 4T1 breast cancer mouse. KXS was given (1 g/kg) daily by gavage over three weeks starting at the first week while giving DOX. The Morris water maze task was performed to measure the CICI-like behaviors. Oxidative stress markers in the hippocampus, inflammatory cytokines in the serum and hippocampus, Nissl staining, immunofluorescence staining, and analysis for Glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 of the hippocampus were examined to explore the effect and mechanism of KXS on DOX-induced CICI. Meanwhile, tumor growth and survival time were tested in this study. Results. CICI-like behaviors induced by DOX occurred earlier and were severer than the cognitive impairment induced by the tumor, and the effect of KXS on improving the cognitive impairment was obvious. KXS protected against DOX-induced neuroinflammation by decreasing levels of proinflammatory cytokines interleukin-6, interleukin-12p70, and tumor necrosis factor-alpha in both serum and brain and interleukin-1β in the brain, increasing the anti-inflammatory cytokines interleukin-4 in the serum and interleukin-10 in the hippocampus, and inhibiting the astrocytic hyperplasia and microglial polarization in the hippocampus. KXS reduced neural degeneration and protected against DOX-induced oxidative stress according to decreased malondialdehyde level, increased glutathione level, and enhanced activities of superoxide dismutase, catalase, and glutathione peroxidase. Moreover, KXS recovered the lost body weights after DOX administration and prolonged the survival times of mice. Conclusions. KXS may attenuate DOX-induced cognitive impairment by regulating inflammatory responses and reducing oxidative stress and neural degeneration. These findings also presented the role of KXS in improving the quality of life and prolonging survival time in breast cancer mice that received chemotherapy.

Glial cells modulate retinal cell survival in rotenone-induced neural degeneration

Administration of the mitochondrial complex I inhibitor rotenone provides an excellent model to study the pathomechanism of oxidative stress-related neural degeneration diseases. In this study, we examined the glial roles in retinal cell survival and degeneration under the rotenone-induced oxidative stress condition. Mouse-derived Müller, microglial (BV-2), and dissociated retinal cells were used for in vitro experiments. Gene expression levels and cell viability were determined using quantitative reverse transcription-polymerase chain reaction and the alamarBlue assay, respectively. Conditioned media were prepared by stimulating glial cells with rotenone. Retinal ganglion cells (RGCs) and inner nuclear layer (INL) were visualized on rat retinal sections by immunohistochemistry and eosin/hematoxylin, respectively. Rotenone dose-dependently induced glial cell death. Treatment with rotenone or rotenone-stimulated glial cell-conditioned media altered gene expression of growth factors and inflammatory cytokines in glial cells. The viability of dissociated retinal cells significantly increased upon culturing in media conditioned with rotenone-stimulated or Müller cell-conditioned media-stimulated BV-2 cells. Furthermore, intravitreal neurotrophin-5 administration prevented the rotenone-induced reduction of RGC number and INL thickness in rats. Thus, glial cells exerted both positive and negative effects on retinal cell survival in rotenone-induced neural degeneration via altered expression of growth factors, especially upregulation of microglia-derived Ntf5, and proinflammatory cytokines.

Delayed development of aphasia related to degeneration of the arcuate fasciculus in the dominant hemisphere nine years after the onset in a patient with intracerebral hemorrhage: a case report

Background We report on a patient with an intracerebral hemorrhage (ICH), who showed delayed development of aphasia, which was demonstrated via follow up diffusion tensor tractography (DTT) to be related to neural degeneration of the arcuate fasciculus (AF). Case presentation A 51-year-old, right-handed male presented with right hemiparesis, which occurred at the onset of a spontaneous ICH in the left corona radiata and basal ganglia. Brain magnetic resonance images showed a hematoma in the left subcortical area at one month after onset and hemosiderin deposits in the left subcortical area at nine years after onset. At four weeks after onset, he exhibited severe aphasia, and Western Aphasia Battery (WAB) testing revealed an aphasia quotient in the 39.6 percentile (%ile). However, his aphasia improved to nearly a normal state, and at three months after onset, his aphasia quotient was in the 90.5 %ile. At approximately eight years after onset, he began to show aphasia, and his aphasia increased slowly with time resulting in a WAB aphasia quotient in the 12.5 %ile at nine years after onset. The integrity of the left AF over the hematoma was preserved on 1-month post-onset DTT. However, the middle portion of the left AF in the middle of the hemosiderin deposits showed discontinuation on 9-year post-onset DTT. The fractional anisotropy value of the left AF was higher on the 9-year post-onset DTT (0.48) than that on the 1-month post-onset DTT (0.35), whereas the mean diffusivity value was lower on the 9-year post-onset DTT (0.10) than that on the 1-month post-onset DTT (0.32). The fiber number of the left AF was decreased to 175 on the 9-year post-onset DTT from 239 on the 1-month post-onset DTT. Conclusions We report on a patient with ICH who showed delayed development of aphasia, which appeared to be related to degeneration of the AF in the dominant hemisphere. Our results suggest that DTT would be useful in ruling out neural degeneration of the AF.

Glial Cells Modulate Retinal Cell Survival in Rotenone-Induced Neural Degeneration

Administration of the mitochondrial complex I inhibitor rotenone provides an excellent model to study the pathomechanism of oxidative stress-related neural degeneration diseases. In this study, we examined the glial roles in retinal cell survival and degeneration under the rotenone-induced oxidative stress condition. Mouse-derived Müller, microglial (BV-2), and dissociated retinal cells were used for in vitro experiments. Gene expression levels and cell viability were determined using quantitative reverse transcription-polymerase chain reaction and the alamarBlue assay, respectively. Conditioned media were prepared by stimulating glial cells with rotenone. Retinal ganglion cells (RGCs) and inner nuclear layer (INL) were visualized on rat retinal sections by immunohistochemistry and eosin/hematoxylin, respectively. Rotenone dose-dependently induced glial cell death. Treatment with rotenone or rotenone-stimulated glial cell-conditioned media altered gene expression of growth factors and inflammatory cytokines in glial cells. The viability of dissociated retinal cells significantly increased upon culturing in media conditioned with rotenone-stimulated or Müller cell-conditioned media-stimulated BV-2 cells. Furthermore, intravitreal neurotrophin-5 administration prevented the rotenone-induced reduction of RGC number and INL thickness in rats. Thus, glial cells exerted both positive and negative effects on retinal cell survival in rotenone-induced neural degeneration via altered expression of growth factors, especially upregulation of microglia-derived Ntf5, and proinflammatory cytokines.