istradefylline and Huntington-Disease

The initial goal of this study was to investigate alterations in adenosine A

Topics: Adenosine; Adenosine A2 Receptor Antagonists; Animals; Biomarkers; Corpus Striatum; Disease Models, Animal; Gene Expression Regulation; Humans; Huntingtin Protein; Huntington Disease; Locomotion; Nucleoside Transport Proteins; Prefrontal Cortex; Psychomotor Disorders; Purines; Rats; Rats, Transgenic; Receptor, Adenosine A2A; Triazines; Triazoles; Trinucleotide Repeat Expansion; Tritium

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

Huntington disease (HD) is a neurodegenerative disorder involving preferential loss of striatal GABAergic medium spiny neurons. Adenosine A(2A) receptors (A(2A)Rs) are present in the striatum at both presynaptic and post-synaptic levels. Blocking pre-synaptic A(2A)Rs, localized in glutamatergic terminals that contact striatal GABAergic dynorphinergic neurons, reduces glutamate release, which could be beneficial in HD. On the other hand, blockade of post-synaptic A(2A)Rs, localized in striatal GABAergic enkephalinergic neurons, could exacerbate the motor dysfunction. To evaluate the function of pre- or post-synaptic A(2A)Rs in HD we used selective antagonists for these receptors in a transgenic rat model of HD. Locomotor activity after systemic administration of the postsynaptic A(2A)R antagonist KW-6002 was used to investigate the function of post-synaptic A(2A)Rs. The role of pre-synaptic A(2A)Rs was instead evaluated by measuring the reduction of the electromyographic response of mastication muscles during electrical stimulation of the orofacial motor cortex after the systemic administration of the presynaptic A(2A)R antagonist SCH-442416. The ability of KW-6002 to produce locomotor activation was lost at 6 and 12 month-old of age in heterozygous and homozygous transgenic rats, but not in wild-type littermates. Nevertheless, no significant changes were observed up to 12 months of age in the potency of SCH-442416 to decrease the electromyographic response after cortical electrical stimulation. These results agree with a selective impairment of the striatal GABAergic enkephalinergic neuronal function during pre-symptomatic stages in HD. Since presynaptic A(2A)R function is not impaired, this receptor could probably be used as a target for the symptomatic treatment of the disease.

Topics: Adenosine A2 Receptor Antagonists; Animals; Corpus Striatum; Disease Models, Animal; Electric Stimulation; Electromyography; GABAergic Neurons; Huntington Disease; Masticatory Muscles; Motor Activity; Purines; Pyrazoles; Pyrimidines; Rats; Rats, Transgenic; Receptor, Adenosine A2A; Receptors, Presynaptic; Synaptic Transmission; Treatment Outcome