Functions, dysfunctions and possible therapeutic relevance of adenosine A2A receptors in Huntington's disease

Popoli, Patrizia; Blum, David; Martire, Alberto; Ledent, Catherine; Ceruti, Stefania; Abbracchio, Maria P.

doi:10.1016/j.pneurobio.2006.12.005

Cited by 104 publications

(72 citation statements)

References 160 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Rapid, acute downregulation of ADK expression has also been demonstrated after status epilepticus [93], which may increase Ado levels transiently and decrease epileptic activity (initial seizure suppression) by an endogenous astrocyte-based antiseizure mechanism in the brain [27,65]. However, a subsequent high, acute Ado concentration promotes glial activation and astrogliosis, one of the relevant features of the epileptic brain [153], via stimulation of A 2A receptors [154,155]. The expression of ADK by glial fibrillary acidic protein (GFAP)-positive astrocytes and the overexpression of ADK in parallel with the formation of astrogliosis has been observed [27,65,93,156].…”

Section: Modulation Of Adenosine Levels and Epileptic Activity By Metmentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

View full text Add to dashboard Cite

Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

show abstract

Section: Modulation Of Adenosine Levels and Epileptic Activity By Metmentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

View full text Add to dashboard Cite

show abstract

“…The latter 2 pathways are strongly activated in striatal neurons following treatment with BDNF [104] and are likely protective in HD. Also relevant to HD, adenosine A2a receptors transactivate TrkB, and their blockade reduces sensitivity to excitotoxicity in several models, which thereby also implicate TrkB activation [184][185][186]. 3) R6/1;BDNF +/-mice have 50 % of the normal BDNF level, and are resistant to QA injection relative to R6/1;BDNF +/+ mice, at the pre-symptomatic stage [187,188].…”

Section: How Might Abnormal Bdnf/trkb Neurotransmission Intersect Witmentioning

confidence: 99%

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Ehrlich

2012

Neurotherapeutics

120

View full text Add to dashboard Cite

Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is >40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum. characterized by selective, or perhaps better described as differential [2], vulnerability with degeneration and death of the medium spiny neuron (MSN). The Gamma-aminobutyric acid (GABA)ergic MSN represents 95% of striatal neurons. They are all output neurons, with extensive intra-striatal connections with other MSNs and striatal interneurons. For the last two decades, increased attention has been paid to the pathology in the cortex (particularly in layers V and VI [3]), which contains the corticostriatal projection neurons.Prior to identification of the HTT gene, the huntingtin protein, and the nature of its mutation, it was assumed that selective neuronal vulnerability in HD would be conferred by the expression pattern of the mutated protein (polyQ-htt). As it is now apparent, htt is expressed throughout the nervous system and periphery, without a preference for, or higher level in, MSNs or cortical projection neurons [4].In the absence of enriched expression of a mutated protein, neuronal subtype vulnerability was assumed to arise from unique protein interactions. For example, in the study of another polyQ disease, spinocerebellar ataxia 7, the interaction between ataxin-7 and the homeobox protein CRX in the retina was reported to specifically lead to pathology [5]. In a followup study, the specific role of CRX was not confirmed [6]. To complicate matters further, the same group recently demonstrated that the interactions between a mutant polyQ protein, Ataxin-1, and 14-3-3epsilon differentially affects disease state in cerebellum and brainstem, both of which are vulnerable regions [7]. The regional distribution of the described huntingtin interacting proteins by and large does not explain MSN vulnerability [8][9][10]. One exception is the htt interacting protein RASD2/Rhes (Ras homologue enriched in striatum), which is striatal-specific. It is a small G-protein that mediates sumoylation of polyQ-htt, and thereby its neurotoxicity.

show abstract

“…Thus, activation of the A 2A R potentiates synaptic actions of brain-derived neurotrophic factor (BDNF) in the hippocampus (Diogenes et al, 2007), stimulates glutamate outflow and leads to excessive glial activation (Popoli et al, 2007). In rat cortex, micro-infusion of the potent A 2A R agonist 5′-(Ncyclopropyl)-carboxamidoadenosine (CPCA) increased astrogliosis, an effect that was abolished by co-infusion of the adenosine A 2A R antagonist 1,3-dipropyl-7-methylxanthine (DPMX) (Hindley et al, 1994).…”

Section: Astrogliosismentioning

confidence: 99%

The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

208

210

View full text Add to dashboard Cite

Current therapies for epilepsy are largely symptomatic and do not affect the underlying mechanisms of disease progression, i.e. epileptogenesis. Given the large percentage of pharmacoresistant chronic epilepsies, novel approaches are needed to understand and modify the underlying pathogenetic mechanisms. Although different types of brain injury (e.g. status epilepticus, traumatic brain injury, stroke) can trigger epileptogenesis, astrogliosis appears to be a homotypic response and hallmark of epilepsy. Indeed, recent findings indicate that epilepsy might be a disease of astrocyte dysfunction. This review focuses on the inhibitory neuromodulator and endogenous anticonvulsant adenosine, which is largely regulated by astrocytes and its key metabolic enzyme adenosine kinase (ADK). Recent findings support the "ADK hypothesis of epileptogenesis": (i) Mouse models of epileptogenesis suggest a sequence of events leading from initial downregulation of ADK and elevation of ambient adenosine as an acute protective response, to changes in astrocytic adenosine receptor expression, to astrocyte proliferation and hypertrophy (i.e. astrogliosis), to consequential overexpression of ADK, reduced adenosine and -finally -to spontaneous focal seizure activity restricted to regions of astrogliotic overexpression of ADK. (ii) Transgenic mice overexpressing ADK display increased sensitivity to brain injury and seizures. (iii) Inhibition of ADK prevents seizures in a mouse model of pharmacoresistant epilepsy. (iv) Intrahippocampal implants of stem cells engineered to lack ADK prevent epileptogenesis. Thus, ADK emerges both as a diagnostic marker to predict, as well as a prime therapeutic target to prevent, epileptogenesis.

show abstract

Functions, dysfunctions and possible therapeutic relevance of adenosine A2A receptors in Huntington's disease

Cited by 104 publications

References 160 publications

The Antiepileptic Potential of Nucleosides

The Antiepileptic Potential of Nucleosides

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

The adenosine kinase hypothesis of epileptogenesis

Contact Info

Product

Resources

About