Adenosine Articles 4 - Neural

© 2011

Adenosine as a neuromodulator in neurological diseases

            (Boison 2008) Download

Adenosine is a modulator of brain function uniquely positioned to integrate excitatory and inhibitory neurotransmission. The past few years brought a wealth of new data fostering our understanding of how the adenosine system is involved in the pathogenesis of neurological diseases. Thus, dysregulation of the adenosine system is implicated in epileptogenesis and cell therapies have been developed to locally augment adenosine in an approach to prevent seizures. While activation of inhibitory adenosine A(1) receptors is beneficial in epilepsy, chronic pain and cerebral ischemia, inhibition of facilitatory A(2A) receptors has profound neuroprotective effects, which are currently exploited in clinical trials in Parkinson's disease. A new era of adenosine-based therapies has begun, with the prospect to cover a wide range of neurological diseases.

Adenosine receptor signaling modulates permeability of the blood-brain barrier

            (Carman, Mills et al. 2011) Download

The blood-brain barrier (BBB) is comprised of specialized endothelial cells that form the capillary microvasculature of the CNS and is essential for brain function. It also poses the greatest impediment in the treatment of many CNS diseases because it commonly blocks entry of therapeutic compounds. Here we report that adenosine receptor (AR) signaling modulates BBB permeability in vivo. A(1) and A(2A) AR activation facilitated the entry of intravenously administered macromolecules, including large dextrans and antibodies to beta-amyloid, into murine brains. Additionally, treatment with an FDA-approved selective A(2A) agonist, Lexiscan, also increased BBB permeability in murine models. These changes in BBB permeability are dose-dependent and temporally discrete. Transgenic mice lacking A(1) or A(2A) ARs showed diminished dextran entry into the brain after AR agonism. Following treatment with a broad-spectrum AR agonist, intravenously administered anti-beta-amyloid antibody was observed to enter the CNS and bind beta-amyloid plaques in a transgenic mouse model of Alzheimer's disease (AD). Selective AR activation resulted in cellular changes in vitro including decreased transendothelial electrical resistance, increased actinomyosin stress fiber formation, and alterations in tight junction molecules. These results suggest that AR signaling can be used to modulate BBB permeability in vivo to facilitate the entry of potentially therapeutic compounds into the CNS. AR signaling at brain endothelial cells represents a novel endogenous mechanism of modulating BBB permeability. We anticipate these results will aid in drug design, drug delivery and treatment options for neurological diseases such as AD, Parkinson's disease, multiple sclerosis and cancers of the CNS.

Neuroprotection by adenosine in the brain: From A(1) receptor activation to A (2A) receptor blockade

            (Cunha 2005) Download

Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A(1) receptors (A(1)Rs) and the less abundant, but widespread, facilitatory A(2A)Rs. It is commonly assumed that A(1)Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A(1)R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A(1)Rs in chronic noxious situations. In contrast, A(2A)Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A(2A)R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A(2A)R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A(2A)R blockade compared to A(1)R activation does not mean that A(1)R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A(2A)R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A(1)Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.

The role and regulation of adenosine in the central nervous system

            (Dunwiddie and Masino 2001) Download

Adenosine is a modulator that has a pervasive and generally inhibitory effect on neuronal activity. Tonic activation of adenosine receptors by adenosine that is normally present in the extracellular space in brain tissue leads to inhibitory effects that appear to be mediated by both adenosine A1 and A2A receptors. Relief from this tonic inhibition by receptor antagonists such as caffeine accounts for the excitatory actions of these agents. Characterization of the effects of adenosine receptor agonists and antagonists has led to numerous hypotheses concerning the role of this nucleoside. Previous work has established a role for adenosine in a diverse array of neural phenomena, which include regulation of sleep and the level of arousal, neuroprotection, regulation of seizure susceptibility, locomotor effects, analgesia, mediation of the effects of ethanol, and chronic drug use.

Pathophysiological roles for purines: adenosine, caffeine and urate

            (Morelli, Carta et al. 2010) Download

The motor symptoms of Parkinson's disease (PD) are primarily due to the degeneration of the dopaminergic neurons in the nigrostriatal pathway. However, several other brain areas and neurotransmitters other than dopamine such as noradrenaline, 5-hydroxytryptamine and acetylcholine are affected in the disease. Moreover, adenosine because of the extensive interaction of its receptors with the dopaminergic system has been implicated in the pathophysiology of the disease. Based on the involvement of these non-dopaminergic neurotransmitters in PD and the sometimes severe adverse effects that limit the mainstay use of dopamine-based anti-parkinsonian treatments, recent assessments have called for a broadening of therapeutic options beyond the traditional dopaminergic drug arsenal. In this review we describe the interactions between dopamine and adenosine receptors that underpin the pre-clinical and clinical rationale for pursuing adenosine A(2A) receptor antagonists as symptomatic and potentially neuroprotective treatment of PD. The review will pay particular attention to recent results regarding specific A(2A) receptor-receptor interactions and recent findings identifying urate, the end product of purine metabolism, as a novel prognostic biomarker and candidate neuroprotectant in PD.

European Stroke Prevention Study-2 results: serendipitous demonstration of neuroprotection induced by endogenous adenosine accumulation?

            (Picano and Abbracchio 1998) Download

In patients with prior stroke or transient ischaemic attack, anti-platelet treatment with dipyridamole substantially reduced stroke recurrence, with a beneficial effect comparable to and additive with that induced by aspirin (the European Stroke Prevention Study-2). Eugenio Picano and Maria Abbracchio present here a platelet-independent hypothesis, according to which cardiovascular and neuroprotective actions achieved by dipyridamole through chronic elevation of endogenous adenosine levels may have contributed to the therapeutic success of this study.


Caffeine and adenosine

            (Ribeiro and Sebastiao 2010) Download

Caffeine causes most of its biological effects via antagonizing all types of adenosine receptors (ARs): A1, A2A, A3, and A2B and, as does adenosine, exerts effects on neurons and glial cells of all brain areas. In consequence, caffeine, when acting as an AR antagonist, is doing the opposite of activation of adenosine receptors due to removal of endogenous adenosinergic tonus. Besides AR antagonism, xanthines, including caffeine, have other biological actions: they inhibit phosphodiesterases (PDEs) (e.g., PDE1, PDE4, PDE5), promote calcium release from intracellular stores, and interfere with GABA-A receptors. Caffeine, through antagonism of ARs, affects brain functions such as sleep, cognition, learning, and memory, and modifies brain dysfunctions and diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, Epilepsy, Pain/Migraine, Depression, Schizophrenia. In conclusion, targeting approaches that involve ARs will enhance the possibilities to correct brain dysfunctions, via the universally consumed substance that is caffeine.

Adenosine kinase determines the degree of brain injury after ischemic stroke in mice

            (Shen, Lusardi et al. 2011) Download

Adenosine kinase (ADK) is the major negative metabolic regulator of the endogenous neuroprotectant and homeostatic bioenergetic network regulator adenosine. We used three independent experimental approaches to determine the role of ADK as a molecular target for predicting the brain's susceptibility to ischemic stroke. First, when subjected to a middle cerebral artery occlusion model of focal cerebral ischemia, transgenic fb-Adk-def mice, which have increased ADK expression in striatum (164%) and reduced ADK expression in cortical forebrain (65%), demonstrate increased striatal infarct volume (126%) but almost complete protection of cortex (27%) compared with wild-type (WT) controls, indicating that cerebral injury levels directly correlate to levels of ADK in the CNS. Second, we demonstrate abrogation of lipopolysaccharide (LPS)-induced ischemic preconditioning in transgenic mice with brain-wide ADK overexpression (Adk-tg), indicating that ADK activity negatively regulates LPS-induced tolerance to stroke. Third, using adeno-associated virus-based vectors that carry Adk-sense or -antisense constructs to overexpress or knockdown ADK in vivo, we demonstrate increased (126%) or decreased (51%) infarct volume, respectively, 4 weeks after injection into the striatum of WT mice. Together, our data define ADK as a possible therapeutic target for modulating the degree of stroke-induced brain injury.


The role of extracellular adenosine in chemical neurotransmission in the hippocampus and Basal Ganglia: pharmacological and clinical aspects

            (Sperlagh and Vizi 2011) Download

Now there is general agreement that the purine nucleoside adenosine is an important neuromodulator in the central nervous system, playing a crucial role in neuronal excitability and synaptic/non-synaptic transmission in the hippocampus and basal ganglia. Adenosine is derived from the breakdown of extra- or intracellular ATP and is released upon a variety of physiological and pathological stimuli from neuronal and non-neuronal sources, i.e. from glial cells and exerts effects diffusing far away from release sites. The resultant elevation of adenosine levels in the extracellular space reaches micromolar level, and leads to the activation A(1), A(2A), A(2B) and A(3) receptors, localized to pre- and postsynaptic as well as extrasynaptic sites. Activation of presynaptic A(1) receptors inhibits the release of the majority of transmitters including glutamate, acetylcholine, noradrenaline, 5-HT and dopamine, whilst the stimulation of A(2A) receptors facilitates the release of glutamate and acetylcholine and inhibits the release of GABA. These actions underlie modulation of neuronal excitability, synaptic plasticity and coordination of neural networks and provide intriguing target sites for pharmacological intervention in ischemia and Parkinson's disease. However, despite that adenosine is also released during ischemia, A(1) adenosine receptors do not participate in the modulation of excitotoxic glutamate release, which is nonsynaptic and is due to the reverse operation of transporters. Instead, extrasynaptic A(1) receptors might be responsible for the neuroprotection afforded by A(1) receptor activation.

Adenosine and stroke: maximizing the therapeutic potential of adenosine as a prophylactic and acute neuroprotectant

            (Williams-Karnesky and Stenzel-Poore 2009) Download

Stroke is a leading cause of morbidity and mortality in the United States. Despite intensive research into the development of treatments that lessen the severity of cerebrovascular injury, no major therapies exist. Though the potential use of adenosine as a neuroprotective agent in the context of stroke has long been realized, there are currently no adenosine-based therapies for the treatment of cerebral ischemia and reperfusion. One of the major obstacles to developing adenosine-based therapies for the treatment of stroke is the prevalence of functional adenosine receptors outside the central nervous system. The activities of peripheral immune and vascular endothelial cells are particularly vulnerable to modulation via adenosine receptors. Many of the pathophysiological processes in stroke are a direct result of peripheral immune infiltration into the brain. Ischemic preconditioning, which can be induced by a number of stimuli, has emerged as a promising area of focus in the development of stroke therapeutics. Reprogramming of the brain and immune responses to adenosine signaling may be an underlying principle of tolerance to cerebral ischemia. Insight into the role of adenosine in various preconditioning paradigms may lead to new uses for adenosine as both an acute and prophylactic neuroprotectant.


References

        

Boison, D. (2008). "Adenosine as a neuromodulator in neurological diseases." Curr Opin Pharmacol 8(1): 2-7.

Carman, A. J., J. H. Mills, et al. (2011). "Adenosine receptor signaling modulates permeability of the blood-brain barrier." J Neurosci 31(37): 13272-80.

Cunha, R. A. (2005). "Neuroprotection by adenosine in the brain: From A(1) receptor activation to A (2A) receptor blockade." Purinergic Signal 1(2): 111-34.

Dunwiddie, T. V. and S. A. Masino (2001). "The role and regulation of adenosine in the central nervous system." Annu Rev Neurosci 24: 31-55.

Morelli, M., A. R. Carta, et al. (2010). "Pathophysiological roles for purines: adenosine, caffeine and urate." Prog Brain Res 183: 183-208.

Picano, E. and M. P. Abbracchio (1998). "European Stroke Prevention Study-2 results: serendipitous demonstration of neuroprotection induced by endogenous adenosine accumulation?" Trends Pharmacol Sci 19(1): 14-6.

Ribeiro, J. A. and A. M. Sebastiao (2010). "Caffeine and adenosine." J Alzheimers Dis 20 Suppl 1: S3-15.

Shen, H. Y., T. A. Lusardi, et al. (2011). "Adenosine kinase determines the degree of brain injury after ischemic stroke in mice." J Cereb Blood Flow Metab 31(7): 1648-59.

Sperlagh, B. and E. S. Vizi (2011). "The role of extracellular adenosine in chemical neurotransmission in the hippocampus and Basal Ganglia: pharmacological and clinical aspects." Curr Top Med Chem 11(8): 1034-46.

Williams-Karnesky, R. L. and M. P. Stenzel-Poore (2009). "Adenosine and stroke: maximizing the therapeutic potential of adenosine as a prophylactic and acute neuroprotectant." Curr Neuropharmacol 7(3): 217-27.