istradefylline and Memory-Disorders

Working memory (WM) taps into multiple executive processes including encoding, maintenance, and retrieval of information, but the molecular and circuit modulation of these WM processes remains undefined due to the lack of methods to control G protein-coupled receptor signaling with temporal resolution of seconds.. Optogenetic activation of striatopallidal A. The A

Topics: Action Potentials; Adenosine A2 Receptor Antagonists; Animals; Corpus Striatum; Disease Models, Animal; Enkephalins; Female; Macaca fascicularis; Male; Maze Learning; Memory Disorders; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, Transgenic; MPTP Poisoning; Nerve Tissue Proteins; Prefrontal Cortex; Purines; Receptor, Adenosine A2A; Spatial Memory

Adenosine A

Topics: Adenosine A2 Receptor Antagonists; Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Brain; Female; Humans; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Plaque, Amyloid; Purines; Receptor, Adenosine A2A

Cognitive impairments in Huntington's disease (HD) are attributed to a dysfunction of the cortico-striatal pathway and significantly affect the quality of life of the patients, but this has not been a therapeutic focus in HD to date. We postulated that adenosine A(2A) receptors (A(2A)R), located at pre- and post-synaptic elements of the cortico-striatal pathways, modulate striatal neurotransmission and synaptic plasticity and cognitive behaviors. To critically evaluate the ability of A(2A)R inactivation to prevent cognitive deficits in early HD, we cross-bred A(2A)R knockout (KO) mice with two R6/2 transgenic lines of HD (CAG120 and CAG240) to generate two double transgenic R6/2-CAG120-A(2A)R KO and R6/2-CAG240-A(2A)R KO mice and their corresponding wild-type (WT) littermates. Genetic inactivation of A(2A)R prevented working memory deficits induced by R6/2-CAG120 at post-natal week 6 and by R6/2-CAG240 at post-natal month 2 and post-natal month 3, without modifying motor deficits. Similarly the A2(A)R antagonist KW6002 selectively reverted working memory deficits in R6/2-CAG240 mice at post-natal month 3. The search for possible mechanisms indicated that the genetic inactivation of A(2A)R did not affect ubiquitin-positive neuronal inclusions, astrogliosis or Thr-75 phosphorylation of DARPP-32 in the striatum. Importantly, A(2A)R blockade preferentially controlled long-term depression at cortico-striatal synapses in R6/2-CAG240 at post-natal week 6. The reported reversal of working memory deficits in R6/2 mice by the genetic and pharmacological inactivation of A(2A)R provides a proof-of-principle for A(2A)R as novel targets to reverse cognitive deficits in HD, likely by controlling LTD deregulation.

Topics: Adenosine A2 Receptor Antagonists; Animals; Astrocytes; Cerebral Cortex; Cognition Disorders; Corpus Striatum; Disease Models, Animal; Disease Progression; Gliosis; Huntington Disease; Inclusion Bodies; Long-Term Synaptic Depression; Male; Memory Disorders; Memory, Short-Term; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Purines; Receptor, Adenosine A2A; Ubiquitin

Altered cognitive function is a common feature of both the early and later stages of Parkinson's disease (PD) that involves alterations in cortical dopamine content. Adenosine A2A antagonists, such as istradefylline, improve motor function in PD, but their effect on cognitive impairment has not been determined.. The present study investigated whether impairment of working memory due to the loss of dopaminergic input into the prefrontal cortex (PFC) is reversed by administration of istradefylline. We also evaluated whether A2A antagonist administration modulates dopamine levels in the PFC.. Bilateral lesions of the dopaminergic input to the PFC were produced in rats using 6-hydroxydopamine (6-OHDA). Cognitive performance was evaluated using an object recognition task and delayed alternation task. The effects of istradefylline, donepezil and methamphetamine on cognitive performance were examined. In addition, the effect of istradefylline on extracellular dopamine levels in the PFC was studied.. PFC dopamine levels and cognitive performance were significantly reduced by 6-OHDA lesioning. Istradefylline, donepezil and methamphetamine improved cognitive performance of PFC-lesioned rats. Istradefylline increased dopamine levels in the PFC in both normal and PFC-lesioned rats.. PFC dopaminergic input plays an important role in working memory performance. Blockade of A2A receptors using istradefylline reverses the changes in cognitive function, and this may be due to an increase in PFC dopamine content. Adenosine A2A receptor antagonists not only improve motor performance in PD but may also lead to improved cognition.

Topics: Adenosine A2 Receptor Antagonists; Animals; Cognition; Cognition Disorders; Disease Models, Animal; Donepezil; Dopamine; Indans; Male; Memory Disorders; Memory, Short-Term; Methamphetamine; Oxidopamine; Piperidines; Prefrontal Cortex; Purines; Rats; Rats, Sprague-Dawley

Seizures early in life cause long-term behavioral modifications, namely long-term memory deficits in experimental animals. Since caffeine and adenosine A(2A) receptor (A(2A)R) antagonists prevent memory deficits in adult animals, we now investigated if they also prevented the long-term memory deficits caused by a convulsive period early in life. Administration of kainate (KA, 2 mg/kg) to 7-days-old (P7) rats caused a single period of self-extinguishable convulsions which lead to a poorer memory performance in the Y-maze only when rats were older than 90 days, without modification of locomotion or anxiety-like behavior in the elevated-plus maze. In accordance with the relationship between synaptotoxicity and memory dysfunction, the hippocampus of these adult rats treated with kainate at P7 displayed a lower density of synaptic proteins such as SNAP-25 and syntaxin (but not synaptophysin), as well as vesicular glutamate transporters type 1 (but not vesicular GABA transporters), with no changes in PSD-95, NMDA receptor subunits (NR1, NR2A, NR2B) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor subunits (GluR1, GluR2) compared with controls. Caffeine (1 g/L) or the A(2A)R antagonist, KW6002 (3 mg/kg) applied in the drinking water from P21 onwards, prevented these memory deficits in P90 rats treated with KA at P7, as well as the accompanying synaptotoxicity. These results show that a single convulsive episode in early life causes a delayed memory deficit in adulthood accompanied by a glutamatergic synaptotoxicity that was prevented by caffeine or adenosine A(2A)R antagonists.

Topics: Adenosine A2 Receptor Antagonists; Analysis of Variance; Animals; Animals, Newborn; Caffeine; Disease Models, Animal; Disease Progression; Drug Administration Schedule; Glial Fibrillary Acidic Protein; Kainic Acid; Memory Disorders; Neurotoxicity Syndromes; Phosphodiesterase Inhibitors; Purines; Pyrimidines; Qa-SNARE Proteins; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Synapses; Synaptophysin; Synaptosomal-Associated Protein 25; Triazoles; Tritium; Xanthines

Adenosine A2A receptor antagonists alleviate memory deficits caused by aging or by administration of beta-amyloid peptides in rodents, which is in accordance with the beneficial effects of caffeine consumption (an adenosine receptor antagonist) on memory performance in aged individuals and in preventing Alzheimer's disease. We now tested if A2A receptor blockade affords a general beneficial effect in different experimental paradigms disturbing memory performance in rodents. The beta-amyloid fragment present in patients with Alzheimer's disease (Abeta1-42, 2 nmol, icv) decreased spontaneous alternation in the Y-maze after 15 days (29%) to an extent similar to the decrease of memory performance caused by scopolamine (2 mg/kg, ip) or MK-801 (0.25 mg/kg, ip) after 30 min (28% and 39%, respectively). The selective A2A receptor antagonist SCH58261 (0.05 mg/kg, ip every 24 h, starting 30 min before the noxious stimuli) prevented Abeta1-42-induced amnesia, but failed to modify scopolamine- or MK-801-induced amnesia. Similar conclusions were reached when testing another A2A receptor antagonist (KW6002, 3 mg/kg, ip). These results indicate that A2A receptors do not affect general processes of memory impairment but instead play a crucial role restricted to neurodegenerative conditions involving an insidious synaptic deterioration leading to memory dysfunction.

Topics: Adenosine A2 Receptor Antagonists; Amyloid beta-Peptides; Analysis of Variance; Animals; Behavior, Animal; Dizocilpine Maleate; Drug Interactions; Male; Maze Learning; Memory Disorders; Motor Activity; Neuroprotective Agents; Peptide Fragments; Purines; Pyrimidines; Rats; Rats, Wistar; Scopolamine; Triazoles