Upregulation of Adenosine Kinase in Rasmussen Encephalitis

Abstract

Rasmussen encephalitis (RE) is a rare neurologic disorder of childhood characterized by unihemispheric inflammation, progressive neurologic deficits, and intractable focal epilepsy. The pathogenesis of RE is still enigmatic. Adenosine is a key endogenous signaling molecule with anticonvulsive and anti-inflammatory effects, and our previous work demonstrated that dysfunction of the adenosine kinase (ADK)–adenosine system and astrogliosis are the hallmarks of epilepsy. We hypothesized that the epileptogenic mechanisms underlying RE are related to changes in ADK expression and that those changes might be associated with the development of epilepsy in RE patients. Immunohistochemistry was used to examine the expression of ADK and glial fibrillary acidic protein in surgically resected human epileptic cortical specimens from RE patients (n = 12) and compared with control cortical tissues (n = 6). Adenosine kinase expression using Western blot and enzymatic activity for ADK were assessed in RE versus control samples. Focal astrogliosis and marked expression of ADK were observed in the lesions of RE. Significantly greater ADK expression in RE versus controls was demonstrated by Western blot, and greater enzymatic activity for ADK was demonstrated using an enzyme-coupled bioluminescent assay. These results suggest that upregulation of ADK is a common pathologic hallmark of RE and that ADK might be a target in the treatment of epilepsy associated with RE.

Overexpression of Adenosine Kinase in Patients with Epilepsy Associated With Sturge-Weber Syndrome

“…Consistent with previous studies [10,12,24], in white matter of the control group, ADK immunoreactivity was present in sparse astroglial cells with only a weak staining ( Figure 3F); and no positive staining in neuronal cells ( Figure 3E). In SWS specimens, ADK immunoreactivity was remarkably observed in the reactive astroglial cells in the white matter within the lesion area, with a predominant cytoplasmic localization ( Figure 3C, D, inset, arrows).…”

“…Experimental researches demonstrate that overexpression of ADK per se might be sufficient to trigger electrographic seizures [8,15,18,19,22]. Clinical evidence also demonstrates that ADK as a common pathologic hallmark and a target for treatment in intractable epilepsy such as temporal epilepsy [8,9], tumor-Overexpression of Adenosine Kinase in Patients with Epilepsy Associated With Sturge-Weber Syndrome related epilepsy [11], Rasmussen encephalitis [10,24], and focal cortical dysplasia [12].…”

“…Chronic ischemia in the cortical areas affected by leptomeningeal angiomatosis has been usually considered to be the epileptogenic mechanism [7]. Increasing clinical evidence from specimen surgically resected from patients with drug-resistant epilepsy, including temporal lobe epilepsy [8,9], Rasmussen encephalitis [10], astroglial tumorrelated epilepsy [11], and focal cortical dysplasia [12], demonstrated that overexpression of astroglial adenosine kinase (ADK) contributing to seizures generation in human chronic epilepsy. However, in our study, it is first time to literarily report a link between adenosine and SWS.…”

Expression of human cytomegalovirus components in the brain tissues of patients with Rasmussen’s encephalitis

“…The IHC and ISH results were evaluated by following a previously described scoring methodology (Luan and Gao et al, 2013). Cells showing yellow or brown particles in the cytoplasm or nucleus were considered positive and were counted and analyzed using image analysis software (Image-Pro Plus 6.0; Media Cybernetics Inc., Bethesda, USA).…”

“…Several factors are thought to be involved in the occurrence of this syndrome, including virus infection (Walter and Renella, 1989;Farrell et al, 1991), autoantibodies (Rogers et al, 1994), cytotoxic T cells (Bauer et al, 2002;Bien et al, 2002a), and abnormal immune modulation (Luan et al, 2013;Luan et al, 2016). Since various pathological characteristics observed in the brains of patients with RE, such as lymphocyte infiltration, neuron loss, vascular cuffing, and microgliosis (Pardo et al, 2004), are similar to those observed in viral encephalitis, virus infection has been proposed to be an important cause of RE (Rasmussen et al, 1958).…”