Lipopolysaccharide administration for a mouse model of cerebellar ataxia with neuroinflammation

Abstract

Most cerebellar ataxias (cAs) are incurable neurological disorders, resulting in a lack of voluntary control by inflamed or damaged cerebellum. Although CA can be either directly or indirectly related to cerebellar inflammation, there is no suitable animal model of CA with neuroinflammation. In this study, we evaluated the utility of an intracerebellar injection of lipopolysaccharide (LpS) to generate an animal model of inflammatory CA. We observed that LPS administration induced the expression of pro-inflammatory molecules following activation of glial cells. In addition, the administration of LPS resulted in apoptotic purkinje cell death and induced abnormal locomotor activities, such as impaired motor coordination and abnormal hindlimb clasping posture. Our results suggest that intracerebellar LPS administration in experimental animals may be useful for studying the inflammatory component of CA. Cerebellar ataxias (CAs) are motor neuron diseases caused by pathological processes affecting the cerebellum or its associated pathways 1,2. They are characterised by symptoms such as abnormal coordination of balance, movement and gait. Currently, most CAs are incurable, with few exceptions, and only symptom alleviation is possible 3. CAs can be caused by genetic defects, sporadic neurodegenerative disorders, and acquired conditions (for example, infections, toxic reactions, alcohol, and vitamin deficiencies), but they can also arise for unknown reasons 1,3,4. In particular, many reports have shown a close relationship between cerebellar inflammation and CA 1,3,5. The activation of glial cells resulting in the production of pro-inflammatory molecules has been observed in many animal models of CA and is also evident in the cerebellums of patients with CA 6-9. Furthermore, cerebellar inflammation has been shown to induce the loss of Purkinje cells, which results in cerebellar dysfunction 1,7. Although the understanding of CA pathogenesis associated with genetic causes, cerebellar neurotoxicity, and physical damage has contributed to the development of some animal models of CA 1,3 , there is no suitable animal model to study CA following glial activation and neurotoxic cerebellar inflammation in vivo. Neuroinflammation plays a crucial role in the pathogenesis and progression of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease 10. As a potent stimulator of neuroinflammation, lipopolysaccharide (LPS) has been used to mediate neurodegenerative progression 11. An accumulation of evidence has shown that LPS-induced neuroinflammation causes neuronal damage through activation of microglia and astrocytes, M1 microglial polarization and the release of pro-inflammatory mediators. For example, LPS injected into the substantia nigra induces microglia activation, which causes the degeneration of dopamine neurons that constitutes the pathological basis of Parkinson's disease 12. In addition, LPS causes an increase in amyloid beta, which results in demyelination and oligodendrocyte injury in mice brains, w...

Therapeutic Effects of Human Mesenchymal Stem Cells in a Mouse Model of Cerebellar Ataxia with Neuroinflammation

“…To investigate the potential effects of hMSCs against neuroinflammation in the cerebellum of ICA mice, we examined whether the treatment with hMSCs inhibited LPS-induced glial activation 7 days after hMSC transplantation, which was the time point indicated by the inflammatory responses following LPS treatment [ 14 ]. As shown in Figure 3 C, LPS-induced microglial activation was inhibited by hMSC treatment in a dose-dependent manner, whereas reactive astrocytes were not affected by hMSC treatment.…”

“…However, there is no previous study of the effects of MSCs in an animal model of CA associated with neuroinflammation. To assess the therapeutic effects of hMSCs on inflammatory CAs (ICA), we used ICA mice, which were developed in our previous study [ 14 ]. A previous study of ICA mice showed that balance and motor control disabilities, indicating cerebellar dysfunction, were accompanied by the upregulation of proinflammatory molecules via glial activation and followed by apoptotic Purkinje cell loss.…”

“…The aim of this study was to examine the therapeutic potential of hMSCs for LPS-induced ICA model mice [ 14 ]. Animal experiments were conducted to investigate the beneficial effects of hMSCs in the LPS-induced ICA mice by using three to five mice per each group.…”

“…Inflammatory CA was induced by injection of 5 μg LPS in 5 μL of phosphate-buffered saline (PBS) directly into the cerebellum, as described in a previously published procedure with minor modifications [ 14 , 27 ]. Male C57BL/6 mice (approximatedly 20–25 g, 10 weeks old, Daehan Biolink Co., Ltd., Eumseong, Korea) were anesthetized via intraperitoneal administration of a mixture of ketamine (115 mg/kg, Yuhan Corporation, Seoul, Korea) and Rompun (23 mg/kg, Bayer Korea Ltd., Seoul, Korea).…”

“…However, there is currently no appropriate animal model to study CA associated with cerebellar inflammation. Therefore, we have recently developed an inflammatory CA (ICA) animal model induced by lipopolysaccharide (LPS) injected directly into the cerebellum [ 14 ].…”