首都医科大学三博脑科医院癫痫中心 李天富 高青 栾国明

Abstract

Rasmussen’s encephalitis (RE) is neurological disorder of childhood characterized by unihemispheric inflammation, intractable focal epilepsy and progressive cognitive and neurological deficits.Currently,hemispherectomy is the only effective method to date to control the seizures associated with RE. Although this disease has been heavily investigated, the pathogenesis of RE with unilateral cortex atrophy and focal seizure is still enigmatic. Over-expression of the ADK,the major adenosine removing enzyme, was observed in the lesions of RE. As the upper neuromodulator of the brain, adenosine is well known with anti-inflammtion, aniti-epilepsy as well as improving cognitive dysfunction associated with epilepsy. Overexpression of ADK and resulting adenosinedeficiency is involved in the development of REpharmacoresistantseizures, inflammation, and deficits in cognitive.Dysregulation of adenosine signaling, which suggest the specific targets in the treatment of epilepsy, inflammation and cognitive deterioration associated with epilepsy in RE patients.

Key words: Rasmussen encephalitis, adenosine, epilepsy, inflammation,cognition

Introduction

Rasmussen encephalitis (RE) is a very rare chronic progressive inflammatory neurological disorder of uncertain etiology affecting mostly children and associated with hemispheric atrophy, pharmacoresistant focal epilepsy (epilepsiapartialis continua), cognitive deterioration and progressive neurological deficits, resulting from progressive loss of function subserved by the involved cerebral hemisphere. The aetiology and pathogenesis of RE, in particular, the factors responsible for the characteristic of asymmetry are still unclear.Seizures are a prominent clinical features of RE, while the inflammation plays a crucial role in the pathomechanism of epileptogenesis, and clinically comorbid cognition deficits are amongthe most debilitating and persistent concerns of chronicepilepsy associated with RE.Overexpression of ADKandresulting adenosine deficiencyin sclerotic lesion tissue of the RE brain can be animportant factor for the development of pharmacoresistant focal seizure, inflammation and cognitive deterioration. Therefore, focal augmentation of adenosine may be an ideal therapeutic strategy for RE- with anti-seizure, antiinflammation and improve the cognitive deterioration. In the following we will highlight the reasonable mechanistic explanations how adenosine deficiencymight functionally be linked to the development of epilepsy, inflammation and cognition deficits in RE

Adenosine and Epilepsy

Extensive evidence demonstrated that adenosine is an inhibitory modulator of brainactivity, and its anticonvulsant and seizure terminating effects, mediated by both receptordependent and receptor–independentpathways, have been illustrated in experimental models of epilepsy.

Adenosine receptor-dependent pathway

Neuronal excitability in the brain is modulated by activation of G protein coupled adenosine receptors (A1, A2A, A2B,A3). The receptor expression levels and availability of endogenous adenosine to activate the receptors plays a crucial role in neuronal excitability. Imbalance of adenosine receptor activation (decreased A1Rsignaling and increased A2AR signaling) contributes to the pathophysiology and development ofepilepsy. Endogenous adenosine acting at A1R is an important seizure-control mechanism. Currently increased expression of adenosine kinase (ADK)-the main adenosine-removing enzyme, and decreased A1Rsignaling, both contributing to reduce the adenosine tone, are regarded as important factor contributing to the development and pathophysiology ofepilepsyas well as a potential target for anti-epileptogenesis or disease modification.A1R are enriched in the central nervous system, where they are expressed in the cerebral cortex, hippocampus, cerebellum,thalamus, and brainstem. In the brain, adenosine modulates neuronal activity by decreasing presynaptic release of various neurotransmitters, and the most dramatic inhibitory actions are on the glutamatergic system. In addition,adenosine acting through postsynaptic A1Rs may activate K+ channels, leading to hyperpolarization of postsynaptic neurons and promoting NMDA receptor inhibition. Deletion of A1Rs or increased adenosine clearance by overexpression of ADK (which should reduce A1R activation) both cause spontaneous electrographic seizures and develop lethal status epilepticus following the intrahippocampal injection of kainic acid in rodent models of epilepsy.The ability of adenosine to prevent or ameliorate seizures induced by pentylenetetrazole, pilocarpine, NMDA, bicuculline, organophosphate treatment, and electrical stimulation has been attributed essentially to A1 receptor activation, which inhibits presynaptic excitatory neurotransmitter releaseand hyperpolarises the postsynaptic cell membrane. In addition to the several lines of experimental animal research support the important anticonvulsant role of adenosine, increasing clinical evidence from specimen surgically resected from patients with pharmacoresistant epilepsy also demonstrated that adenosine dysfunction contributing to seizure generation in human chronic epilepsy, including i) adenosine deficiency in microdialysis samples from epileptogenic hippocampus in human patients with TLE;ii) overexpression of astroglial ADK within the epileptic foci in temporal lobe epilepsy;Rasmussen encephalitis, astroglial tumor-related epilepsy and focal cortical dysplasia,leading to decrease the adenosine level and A1R activation;iii) genetic variation in ADK associating with posttraumatic epilepsy development and contributing to explaining variability in time to first seizure and posttraumatic epilepsy risk, indicating that genetic variation in adenosine regulatory pathways relating to epileptogenesis and ADK may be the therapeutic targets for pharmacotherapy development; iv) variants in the A1R gene associating with the development of posttraumatic seizures after a severe traumatic brain injury and indicating that deficiency in A1R signaling might be associated with posttraumatic epileptogenesis; v)loss of A1 adenosine receptors in human temporal lobe epilepsy, demonstrating that loss of anticonvulsant A1 receptors may contribute to the human epileptic condition.

Adenosine receptor-independent pathway

In addition to adenosine receptor dependent effects,adenosineexertsreceptor-independenteffectsinDNA methylationhomeostasis. Adenosine is an obligatory end product of S-adenosylmethionine(SAM) dependent transmethylation reactions, which also includemethyl group transfers onto DNA, catalyzed by DNA methyltransferases. Increased ADK expression drives increased the transmethylation pathway leading tohypermethylated DNApotentially implicated in epileptogenesis. Increased ADK and increased DNA methylationstatus form a vicious cycle implicated in the progression andmaintenance of the epileptic state. Therefore, dysregulation of ADKplays a significant role in the processes that turn a normal brain intoan epileptic brain.ThiswouldseemtosuggesttheuseofADK inhibitorsinepilepsytherapy. However, the chronic systemic use of ADK inhibitors might not be a viabletherapeutic option due to liver toxicity, and the occurrence of brain hemorrhage insome of the preclinical studiesaswellasco gnitiveandsedativeadverseeffects. Gene therapy directed to ADK through an antisense oligonucleotide as a means of conserving adenosine by reducing ADK expression has been investigated. Adenosine-releasing polymer implanted to the brain ventricles of epileptic rats demonstrated that focal augmentation of adenosine restores normal DNA methylation and thereby prevents epileptogenesis (Williams-Karnesky et al., 2013). The mechanism of action of Ketogenic diet (KD), an often prescribed protocol to treat pediatric pharmacoresistant epilepsy, involved adenosine receptor-dependent pathway and adenosine receptorindependent pathway. On the one hand, KD downregulates ADKto increase adenosine levels in the brain to enhance adenosinesignaling and A1R activation. On the other hand,KD treatment has been shown to increase adenosine levels and exerts receptor-independent effects in DNA methylation homeostasis to reduce DNA methylation. There is every indication that agents able to increase adenosine availability may have a place in the future treatment of epilepsy via adenosine receptor-dependent pathway and adenosine receptor-independent pathway.

AdenosineandInflammation

Adenosine is an endogenous purine nucleoside that modulates a wide range of physiological functions (7). Most notable among its many roles is its importance in controlling inflammation and inhibiting seizures.Homeostasis of adenosine receptorsignaling is of crucial importance in the regulation ofinflammation and the release of proin flammatorycytokinesreleasefrommacrophages,dendritic cells,andlymphocytes. It is well accepted that adenosine exerts potent anti-inflammatory effectsvia activation of A2A and A3 receptors, and A2A and A3 receptor agonists potentiallyhavingarelevantrole inthetreatmentofrheumat oidarthritis. The A2A and A3 receptors in particular play keyroles in the regulation of inflammatory pathways in avariety of conditions including arthritis. Activation of A2Areceptor prevented the collagen-induced arthritisprogr essionbypreventingnitrosativeandoxidativeinjuryandreduci ng the levels of cytokines such as TNFα, interleukin(IL)1β, therebysuggestingaroleforA2A receptors ininflammation. Alsoadenosine was found to suppress elevated levels ofthe proinflammatory cytokines TNFαand IL-1βinpatients with rheumatoid arthritis.A2B receptor subtypeisselectivelyindu cedininflamed vascularandintestinal epithelia,aswellasthek idneys,heartandlung,makingitadirecttargetinthetreatmentof inflammationcharacterized by tissue hypoxia.

Adenosine and Cognition

Apart from mediatingseizure inhibition and inflammation control, adenosine is a crucial regulator of behavior and disruption of adenosine homeostasis has been linked withcognitive and psychiatric phenotypes. Adenosine, a key upstream modulator of majorneurotransmitter systemsincluding glutamatergic and GABAergic neurotransmission, provide a crucial role in the regulation of cognitive processes. ADK is the primary route of adenosine metabolism in brain and minor changes in ADK activity translate rapidly into major changes in adenosine. Thereby, dysregulation of ADK expression and resultingdisruption of adenosine homeostasis is implicatedin a wide range of neurologic and neuropsychiatricpathologies. The link betweenoverexpression of ADK and cognitive impairmentmight be of pathologic relevance for neurologicconditions in which overexpression of ADK has been confirmed in epilepsy: i) Transgenic overexpressionof ADK in the brain of mice (Adk-tg mice)caused prominent cognitive impairment on severallevels, and Adk-tg mice displayed severe learning deficits in thedomains of reference memory, working memory, andassociative learning, in particular severe learning deficits in the Morris watermaze task and in Pavlovian conditioning. ii) Adenosine releasing cell grafts tothe hippocampal formation to reconstruct of adenosine homeostasis demonstrate cognitive performance improving in Adktransgenicmice; iii) Astrogliosis-associated overexpression ofADK might be causally involved in the development ofcognitive comorbidities in pharmacoresistant epilepsy such as temporal lobe epilepsy, focal cortical dysplasia, Rusmussen encephalitis; iv) Astroglial A2A receptor affects cognitive function through a novel mechanisminvolving astrocyte-driven neuronal adaptation processes. Via controlling astrocytic glutamate transporter-I activity, dysfunction of astrocytic A2AR, triggers an astrocyteto- neuron wave of communication resulting in disrupted glutamate homeostasis.

Acknowledgment

This Project was supported by the Grant from the BIBDPXM2013_014226_07_000084, National Natural Science Foundation of China (81571275), Scientific Research Common Program of Beijing Commission of Education(KM201410025027).We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Competing interests

The authors declare that they have no competing interests.