Neuroprotection mediated by inhibition of calpain during acute viral encephalitis

Howe, Charles L.; LaFrance‐Corey, Reghann G.; Mirchia, Kanish; Sauer, Brian M.; McGovern, Renee M.; Reid, Joel M.; Buenz, Eric J.

doi:10.1038/srep28699

Cited by 20 publications

(27 citation statements)

References 78 publications

(110 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additional studies of Howe et al (2012b) substantiated that neuronal loss during viral encephalitis is not primarily due to direct virus-mediated injury but much of the damage is associated with immune-mediated bystander pathology in response to infiltration of inflammatory monocytes/macrophages. Furthermore, the latter group showed that hippocampal neuron death in these animals is associated with calpain activation (Buenz et al, 2009), leading to the working model that infiltrating inflammatory cells release cytokines and other effector molecules that disrupt hippocampal circuitry, triggering seizures and inducing further disruption of the hippocampal network (Howe et al, 2016). Indeed, treatment with the calpain inhibitor ritonavir significantly reduced calpain activity in the hippocampus, protected hippocampal neurons from death, preserved cognitive performance, and suppressed seizure escalation in the Theiler' virus model (Howe et al, 2016).…”

Section: Brain Analysis Of Infiltrated Macrophages and Activated Micrmentioning

confidence: 99%

Macrophage depletion by liposome-encapsulated clodronate suppresses seizures but not hippocampal damage after acute viral encephalitis

Waltl¹,

Käufer

Bröer

et al. 2018

Neurobiology of Disease

View full text Add to dashboard Cite

Viral encephalitis is a major risk factor for the development of seizures and epilepsy, but the underlying mechanisms are only poorly understood. Mouse models such as viral encephalitis induced by intracerebral infection with Theiler's virus in C57BL/6 (B6) mice allow advancing our understanding of the immunological and virological aspects of infection-induced seizures and their treatment. Previous studies using the Theiler's virus model in B6 mice have indicated that brain-infiltrating inflammatory macrophages and the cytokines released by these cells are key to the development of acute seizures and hippocampal damage in this model. However, approaches used to prevent or reduce macrophage infiltration were not specific, so contribution of other mechanisms could not be excluded. In the present study, we used a more selective and widely used approach for macrophage depletion, i.e., systemic administration of clodronate liposomes, to study the contribution of macrophage infiltration to development of seizures and hippocampal damage. By this approach, almost complete depletion of monocytic cells was achieved in spleen and blood of Theiler's virus infected B6 mice, which was associated with a 70% decrease in the number of brain infiltrating macrophages as assessed by flow cytometry. Significantly less clodronate liposome-treated mice exhibited seizures than liposome controls (P<0.01), but the development of hippocampal damage was not prevented or reduced. Clodronate liposome treatment did not reduce the increased Iba1 and Mac3 labeling in the hippocampus of infected mice, indicating that activated microglia may contribute to hippocampal damage. The unexpected mismatch between occurrence of seizures and hippocampal damage is thought-provoking and suggests that the mechanisms involved in degeneration of specific populations of hippocampal neurons in encephalitis-induced epilepsy are more complex than previously thought.

show abstract

Section: Brain Analysis Of Infiltrated Macrophages and Activated Micrmentioning

confidence: 99%

Macrophage depletion by liposome-encapsulated clodronate suppresses seizures but not hippocampal damage after acute viral encephalitis

Waltl¹,

Käufer

Bröer

et al. 2018

Neurobiology of Disease

View full text Add to dashboard Cite

show abstract

“…However, in contrast to serum, the brain levels rose again at 12 hpi and reached levels comparable to the 3 hpi values by 24 hpi. Based on our previous findings regarding the locus of neuronal injury during acute TMEV infection [7,22], we also measured CCL2 in microdissected hippocampus at the same timepoints in separate animals ( Figure 2C). CCL2 levels peaked at 6 hpi and were measured at 1500 pg per mouse (hippocampi pooled for each individual animal).…”

Section: Tmev Infection Induces Rapid Hippocampal Production and Relementioning

confidence: 99%

“…However, despite essentially complete resolution of the infection, permanent neurological sequelae such as impaired spatial learning [2,4], anxiety [5], and epilepsy [6] occur in most post-infectious animals. Uniquely, these neurologic problems largely stem from bystander loss of CA1 pyramidal neurons and subsequent disruption of hippocampal and hippocampal-cortical circuits [4,7,8].…”

Section: Introductionmentioning

confidence: 99%

Neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection

Howe

LaFrance‐Corey

Goddery

et al. 2017

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Viral encephalitis is a dangerous compromise between the need to robustly clear pathogen from the brain and the need to protect neurons from bystander injury. Theiler's murine encephalomyelitis virus (TMEV) infection of C57Bl/6 mice is a model of viral encephalitis in which the compromise results in hippocampal damage and permanent neurological sequelae. We previously identified brain infiltrating inflammatory monocytes as the primary driver of this hippocampal pathology, but the mechanisms involved in recruiting these cells to the brain were unclear. Methods: Chemokine expression levels in the hippocampus were assessed by microarray, ELISA, RT-PCR, and immunofluorescence. Monocyte infiltration during acute TMEV infection was measured by flow cytometry. CCL2 levels were manipulated by immunodepletion and by specific removal from neurons in mice generated by crossing a line expressing the Cre recombinase behind the synapsin promoter to animals with floxed CCL2. Results: Inoculation of the brain with TMEV induced hippocampal production of the proinflammatory chemokine CCL2 that peaked at 6 hours postinfection, whereas inoculation with UV-inactivated TMEV did not elicit this response. Immunofluorescence revealed that hippocampal neurons expressed high levels of CCL2 at this timepoint. Genetic deletion of CCR2 and systemic immunodepletion of CCL2 abrogated or blunted the infiltration of inflammatory monocytes into the brain during acute infection. Specific genetic deletion of CCL2 from neurons reduced serum and hippocampal CCL2 levels and inhibited inflammatory monocyte infiltration into the brain. Conclusions: We conclude that intracranial inoculation with infectious TMEV rapidly induces the expression of CCL2 in neurons, and this cellular source is necessary for CCR2-dependent infiltration of inflammatory monocytes into the brain during the most acute stage of encephalitis. These findings highlight a unique role for neuronal production of chemokines in the initiation of leukocytic infiltration into the infected central nervous system.

show abstract

“…If our interpretation of these findings is correct, then post-ictal assessment of serum NSE may serve as a surrogate biomarker for measuring the efficacy of acute neuroprotective therapies aimed at preserving neurons in patients with epilepsy 34 . We recently reported that treatment of mice with an oral calpain inhibitor after the start of behavioral seizures induced by the neuroinflammatory response to acute viral infection resulted in preservation of hippocampal CA1 pyramidal neurons, preservation of cognitive performance, and abrogation of further seizure events 35 . Likewise, calpain inhibitor therapy started after onset of status epilepticus reduced seizure burden in the rat pilocarpine model 36 and preserved CA1 neurons in the kainic acid model 37 .…”

Section: Discussionmentioning

confidence: 99%

Systemic evidence of acute seizure-associated neuronal injury in patients with temporal lobe epilepsy

Kunda

LaFrance‐Corey

Khadjevand

et al. 2017

Preprint

View full text Add to dashboard Cite

Patients with drug refractory temporal lobe epilepsy frequently accumulate cognitive impairment over time, suggesting neuronal loss induced by seizures. We measured serum levels of neuronspecific enolase (NSE), a neuronal injury marker, relative to levels of S100β, a marker of glial injury, at 6 AM, 9 AM, noon, 3 PM, and 6 PM over the course of several days in 7 epilepsy patients and 4 healthy controls. All epilepsy patients exhibited significant deviations in NSE levels through time, and 4 of the epilepsy patients exhibited large sample entropy values and large signal variation metrics for NSE relative to S100β. Controls did not exhibit such changes. Correlation analysis revealed that NSE levels were significantly elevated after clinical seizure events. There was also a highly significant relationship between increased EEG spike frequency and an increase in serum NSE levels measured 24 hours later. The detection of large but transient post-ictal increases in NSE suggests that even self-limited seizures may cause an injury to neurons that underlies cognitive decline in some patients. Post-ictal assessment of serum NSE may serve as a biomarker for measuring the efficacy of future acute neuroprotective strategies in epilepsy patients.

show abstract

Neuroprotection mediated by inhibition of calpain during acute viral encephalitis

Cited by 20 publications

References 78 publications

Macrophage depletion by liposome-encapsulated clodronate suppresses seizures but not hippocampal damage after acute viral encephalitis

Macrophage depletion by liposome-encapsulated clodronate suppresses seizures but not hippocampal damage after acute viral encephalitis

Neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection

Systemic evidence of acute seizure-associated neuronal injury in patients with temporal lobe epilepsy

Contact Info

Product

Resources

About