Striatal adenosine A2A receptor involvement in normal and large nest building deer mice: Perspectives on compulsivity and anxiety.

Obsessive-compulsive disorder (OCD) is characterized by recurring obsessive thoughts and repetitive behaviors that are often associated with anxiety and perturbations in cortico-striatal signaling. Given the suboptimal response of OCD to current serotonergic interventions, there is a need to better understand the psychobiological mechanisms that may underlie the disorder. In this regard, investigations into adenosinergic processes might be fruitful. Indeed, adenosine modulates both anxiety- and motor behavioral output. Thus, we aimed to explore the potential associations between compulsive-like large nest building (LNB) behavior in deer mice, anxiety and adenosinergic processes. From an initial pool of 120 adult deer mice, 34 normal nest building (NNB)- and 32 LNB-expressing mice of both sexes were selected and exposed to either a normal water (wCTRL) or vehicle control (vCTRL), lorazepam (LOR) or istradefylline (ISTRA) for 7- (LOR) or 28 days after which nesting assessment was repeated and animals screened for anxiety-like behavior in an anxiogenic open field. Mice were then euthanized, the striatal tissue removed on ice and the adenosine A2A receptor expression quantified. Our findings indicate that NNB and LNB behavior are not distinctly associated with measures of generalized anxiety and that ISTRA-induced changes in nesting expression are dissociated from changes in anxiety scores. Further, data from this investigation show that nesting in deer mice is directly related to striatal adenosine signaling, and that LNB is founded upon a lower degree of adenosinergic A2A stimulation.

Therapeutic potentials of agonist and antagonist of adenosine receptors in type 2 diabetes.

Type 2 diabetes has been a global health challenge over the decades and is among the leading causes of death. Several treatment approaches have been developed, but more effective and new therapies are still needed. The role of adenosine in glucose and lipid homeostasis has offered a different therapeutic approach. Adenosine mediates its physiological role through the activation of adenosine receptors. These adenosine receptors have been implicated in glucose and lipid homeostasis. The ability of agonists and antagonists of adenosine receptors to activate or inhibit the adenosine signalling cascade and thereby affecting the balance of glucose and lipid homeostasis has challenged the studies of agonists and antagonists of adenosine receptors, both preclinical and clinical, as potential anti-diabetic drugs. This review provides a background on different anti-diabetic therapeutic approaches, outlining the role of adenosine receptors in glucose and lipid homeostasis, and mechanisms underlying the action of agonists/antagonists of adenosine receptors as a therapeutic potential towards type 2 diabetes.

5-Substituted 2-benzylidene-1-tetralone analogues as A1 and/or A2A antagonists for the potential treatment of neurological conditions.

Adenosine A1 and A2A receptors are attracting great interest as drug targets for their role in cognitive and motor deficits, respectively. Antagonism of both these adenosine receptors may offer therapeutic benefits in complex neurological diseases, such as Alzheimer's and Parkinson's disease. The aim of this study was to explore the affinity and selectivity of 2-benzylidene-1-tetralone derivatives as adenosine A1 and A2A receptor antagonists. Several 5-hydroxy substituted 2-benzylidene-1-tetralone analogues with substituents on ring B were synthesized and assessed as antagonists of the adenosine A1 and A2A receptors via radioligand binding assays. The results indicated that hydroxy substitution in the meta and para position of phenyl ring B, displayed the highest selectivity and affinity for the adenosine A1 receptor with Ki values in the low micromolar range. Replacement of ring B with a 2-amino-pyrimidine moiety led to compound 12 with an increase of affinity and selectivity for the adenosine A2A receptor. These substitution patterns led to enhanced adenosine A1 and A2A receptor binding affinity. The para-substituted 5-hydroxy analogue 3 behaved as an adenosine A1 receptor antagonists in a GTP shift assay performed with rat whole brain membranes expressing adenosine A1 receptors. In conclusion, compounds 3 and 12, showed the best adenosine A1 and A2A receptor affinity respectively, and therefore represent novel adenosine receptor antagonists that may have potential with further structural modifications as drug candidates for neurological disorders.

Selected C8 two-chain linkers enhance the adenosine A1/A2A receptor affinity and selectivity of caffeine.

Recent research exploring C8 substitution on the caffeine core identified 8-(2-phenylethyl)-1,3,7-trimethylxanthine as a non-selective adenosine receptor antagonist. To elaborate further, we included various C8 two-chain-length linkers to enhance adenosine receptor affinity. The results indicated that the unsubstituted benzyloxy linker (1e A1Ki = 1.52 µM) displayed the highest affinity for the A1 adenosine receptor and the para-chloro-substituted phenoxymethyl (1d A2AKi = 1.33 µM) linker the best A2A adenosine receptor affinity. The position of the oxygen revealed that the phenoxymethyl linker favoured A1 adenosine receptor selectivity over the benzyloxy linker and, by introducing a para-chloro substituent, A2A adenosine receptor selectivity was obtained. Selected compounds (1c, 1e) behaved as A1 adenosine receptor antagonists in GTP shift assays and therefore represent selective and non-selective A1 and A2A adenosine receptor antagonists that may have potential for treating neurological disorders.

Investigating the potential neuroprotective effects of statins on DNA damage in mouse striatum.

We investigated the protective effect of pravastatin, simvastatin and atorvastatin on striatal DNA damage as a potential method to conserve and protect the nigrostriatal neurons. C57Bl/J6 mice were treated with combinations of a statin and the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). DNA damage, DNA sensitivity to H(2)O(2)in vitro, and DNA repair capacity was measured using the single cell gel electrophoresis (comet) assay. MPTP treatment increased DNA damage in the striatum. Contrary to expectation, the statins studied here did not protect DNA against H(2)O(2) induced damage but did in fact cause DNA damage. Treatment with simvastatin showed a significant increase in levels of DNA damage (p < or = 0.0018) and DNA damage induced in vitro with H(2)O(2) was significantly increased by pravastatin (p < or = 0.0001). DNA repair and repair capacity was slightly increased by simvastatin, significantly increased by pravastatin (p=0.0093), but slightly decreased by atorvastatin. In the MPTP treated groups, pre-treated with statins, pravastatin (p < or =0.0036) and simvastatin (p < or = 0.021), increased the level of DNA damage, while atorvastatin did not exhibit a significant effect. All three statins, administered prior to MPTP, offered slight protection against H(2)O(2) induced DNA damage and simvastatin and atorvastatin decreased the DNA repair capacity of the cells insignificantly. Treatment with statins, under the experimental conditions used, increased baseline levels of DNA damage, but DNA repair processes were left intact because the amount of repair also increased. Oxidative damage, however, largely exceeded the extent of DNA repair of mice treated with both the statins and MPTP.