Adenosine is crucial for deep brain stimulation–mediated attenuation of tremor

Abstract

Deep brain stimulation (DBS) is a widely used neurosurgical approach to treating tremor and other movement disorders. In addition, the use of DBS in a number of psychiatric diseases, including obsessive-compulsive disorders and depression, is currently being tested. Despite the rapid increase in the number of individuals with surgically implanted stimulation electrodes, the cellular pathways involved in mediating the effects of DBS remain unknown. Here we show that DBS is associated with a marked increase in the release of ATP, resulting in accumulation of its catabolic product, adenosine. Adenosine A1 receptor activation depresses excitatory transmission in the thalamus and reduces both tremor- and DBS-induced side effects. Intrathalamic infusion of A1 receptor agonists directly reduces tremor, whereas adenosine A1 receptor-null mice show involuntary movements and seizure at stimulation intensities below the therapeutic level. Furthermore, our data indicate that endogenous adenosine mechanisms are active in tremor, thus supporting the clinical notion that caffeine, a nonselective adenosine receptor antagonist, can trigger or exacerbate essential tremor. Our findings suggest that nonsynaptic mechanisms involving the activation of A1 receptors suppress tremor activity and limit stimulation-induced side effects, thereby providing a new pharmacological target to replace or improve the efficacy of DBS.

Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity

“…Notably, the P2 receptor antagonists, pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS; 50 mM) and suramine (50 mM), significantly inhibited astrocytic Ca 2+ waves evoked by HFS [control 85 ± 11 DF/F (%); PPADS 34.9 ± 6.5 DF/F (%), P < 0.01; Suramin 40.7 ± 3.7 DF/F (%), P < 0.05] (Fig. 3C) as previously reported (30,31), suggesting that ATP was indeed present. However, neither of these agents impacted heterosynaptic depression, suggesting that the two events were separate (Fig.…”

Silk polymer-based adenosine release: Therapeutic potential for epilepsy

“…Therefore, focal AATs based on transplanting cells engineered to release adenosine into the vicinity of an epileptogenic focus are effective in preventing seizures, and possibly epileptogenesis [11,13,14]; moreover, AATs are effective in the suppression of seizures that are refractory to commonly used antiepileptic drugs [18,49]. It is important to note that some of the alternative therapeutic approaches mentioned above seem to be based on adenosine augmentation: adenosine is liberated as a consequence of deepbrain stimulation [50] and seems to be involved in the therapeutic effects of the ketogenic diet [47]. Thus, focal AATs hold great promise for the treatment of pharmacoresistant partial epilepsy.…”

Normalization of A2A and A3 adenosine receptor up‐regulation in rheumatoid arthritis patients by treatment with anti–tumor necrosis factor α but not methotrexate

“…The concentrations of adenosine and its metabolites were evaluated according to a well-known method (41,44,45). Under the experimental conditions we used, adenosine levels were increased in plasma samples from all RA patient groups regardless of pharmacologic treatment, which suggests that there is elevated activation of the overexpressed A 2A and A 3 adenosine receptors.…”