adenosine-kinase and Encephalitis

Rasmussen encephalitis (RE) is a rare neurological disorder characterized by unilateral inflammation of cerebral cortex and other structures, most notably the hippocampus, progressive cognitive deterioration, and pharmacoresistant focal epilepsy. The pathogenesis of RE with unilateral cortical atrophy and focal seizures is still enigmatic. Activation of adenosine A1 receptors (A1R) has been proven to prevent the spatial spread of seizures. We hypothesized that the epileptogenic mechanisms underlying RE are related to changes in neuronal A1R expression. Immunnohistochemistry was used to examine the expression of A1R and adenosine kinase (ADK) in cortical specimens from RE (n = 12), and compared with control cortical tissue. The quantification of A1R and ADK expression was evaluated by Western blot. A1R was predominantly localized in perinuclear of neurons and not in astrocytes or microglia. Upregulation of neuronal A1R was observed in the lesions of RE. Reactive astrocytes and subpopulation of remaining neurons demonstrated over-expression of the ADK within the lesions of RE. Significant increase of A1R and ADK expression in RE compared with controls was confirmed by Western blot. These results suggest that over-expression of ADK is a common pathologic hallmark of RE, and that upregulation of neuronal A1R in RE is crucial in preventing the spread of seizures.

Topics: Adenosine Kinase; Adolescent; Calcium-Binding Proteins; Cerebral Cortex; Child; Child, Preschool; Cytokines; DNA-Binding Proteins; Electroencephalography; Encephalitis; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Microfilament Proteins; Nerve Tissue Proteins; Neurons; Receptor, Adenosine A1; Up-Regulation

Acetate supplementation reduces neuroglia activation and pro-inflammatory cytokine expression in rat models of neuroinflammation and Lyme neuroborreliosis. Because single-dose glyceryl triacetate (GTA) treatment increases brain phosphocreatine and reduces brain AMP levels, we postulate that GTA modulates adenosine metabolizing enzymes and receptors, which may be a possible mechanism to reduce neuroinflammation.. To test this hypothesis, we quantified the ability of GTA to alter brain levels of ecto-5'-nucleotidase (CD73), adenosine kinase (AK), and adenosine A2A receptor using western blot analysis and CD73 activity by measuring the rate of AMP hydrolysis. Neuroinflammation was induced by continuous bacterial lipopolysaccharide (LPS) infusion in the fourth ventricle of the brain for 14 and 28 days. Three treatment strategies were employed, one and two where rats received prophylactic GTA through oral gavage with LPS infusion for 14 or 28 days. In the third treatment regimen, an interventional strategy was used where rats were subjected to 28 days of neuroinflammation, and GTA treatment was started on day 14 following the start of the LPS infusion.. We found that rats subjected to neuroinflammation for 28 days had a 28% reduction in CD73 levels and a 43% increase in AK levels that was reversed with prophylactic acetate supplementation. CD73 activity in these rats was increased by 46% with the 28-day GTA treatment compared to the water-treated rats. Rats subjected to neuroinflammation for 14 days showed a 50% increase in levels of the adenosine A2A receptor, which was prevented with prophylactic acetate supplementation. Interventional GTA therapy, beginning on day 14 following the induction of neuroinflammation, resulted in a 67% increase in CD73 levels and a 155% increase in adenosine A2A receptor levels.. These results support the hypothesis that acetate supplementation can modulate brain CD73, AK and adenosine A2A receptor levels, and possibly influence purinergic signaling.

Topics: 5'-Nucleotidase; Acetates; Adenosine Kinase; Analysis of Variance; Animals; Brain; Disease Models, Animal; Drug Administration Routes; Encephalitis; Humans; Lipopolysaccharides; Male; Rats; Rats, Sprague-Dawley; Receptors, Adenosine A2; Time Factors

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.

Topics: Adenosine Kinase; Adolescent; Astrocytes; Cerebral Cortex; Child; Child, Preschool; Encephalitis; Female; Gliosis; Humans; Male; Up-Regulation