ORCID Profile
0000-0003-2550-6422
Current Organisation
Universidade de Coimbra Faculdade de Medicina
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Publications
Exercise attenuates levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned mice
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.NEUROSCIENCE.2013.03.039
Abstract: L-DOPA alleviates the motor symptoms of Parkinson's disease, but its long-term use is associated with undesirable dyskinesia. We now tested whether exercise can attenuate this L-DOPA-induced dyskinesia (LID). We tested the effects of exercise on LID in 6-hydroxydopamine hydrochloride-hemiparkinsonian mice. Animals were treated with L-DOPA/benserazide (25/12.5 mg/kg, i.p.) without and with possibility to exercise (running wheel) during 2 weeks. Exercise drastically prevented the development of LID, and its associated aberrant striatal signaling, namely the hyperphosphorylation of dopamine and cAMP-regulated phosphoprotein 32 kDa protein and c-Fos expression. Our results indicate that exercise can partially prevent the development of LID through the normalization of striatopallidal dopaminergic signaling.
Presynaptic Control of Striatal Glutamatergic Neurotransmission by Adenosine A1–A2AReceptor Heteromers
Publisher: Society for Neuroscience
Date: 15-02-2006
DOI: 10.1523/JNEUROSCI.3574-05.2006
Abstract: The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that heteromerization of adenosine A 1 receptors (A 1 Rs) and A 2A receptors (A 2A Rs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By means of coimmunoprecipitation, bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we showed the existence of A 1 R–A 2A R heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A 1 R and A 2A R are colocalized in the same striatal glutamatergic nerve terminals. Radioligand-binding experiments in cotransfected cells and rat striatum showed that a main biochemical characteristic of the A 1 R–A 2A R heteromer is the ability of A 2A R activation to reduce the affinity of the A 1 R for agonists. This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. Furthermore, it is also shown that A 1 R–A 2A R heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A 1 R–A 2A R heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.
Acyl ghrelin improves cognition, synaptic plasticity deficits and neuroinflammation following amyloid β (Aβ1‐40) administration in mice
Publisher: Wiley
Date: 05-2017
DOI: 10.1111/JNE.12476
Abstract: Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild-type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid β peptide 1-40 (Aβ
Hyperactivation of D1 and A2A receptors contributes to cognitive dysfunction in Huntington's disease
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.NBD.2014.11.004
Abstract: Stimulation of dopamine D1 receptor (D1R) and adenosine A2A receptor (A2AR) increases cAMP-dependent protein kinase (PKA) activity in the brain. In Huntington's disease, by essentially unknown mechanisms, PKA activity is increased in the hippoc us of mouse models and patients and contributes to hippoc al-dependent cognitive impairment in R6 mice. Here, we show for the first time that D1R and A2AR density and functional efficiency are increased in hippoc al nerve terminals from R6/1 mice, which accounts for increased cAMP levels and PKA signaling. In contrast, PKA signaling was not altered in the hippoc us of Hdh(Q7/Q111) mice, a full-length HD model. In line with these findings, chronic (but not acute) combined treatment with D1R plus A2AR antagonists (SCH23390 and SCH58261, respectively) normalizes PKA activity in the hippoc us, facilitates long-term potentiation in behaving R6/1 mice, and ameliorates cognitive dysfunction. By contrast, chronic treatment with either D1R or A2AR antagonist alone does not modify PKA activity or improve cognitive dysfunction in R6/1 mice. Hyperactivation of both D1R and A2AR occurs in HD striatum and chronic treatment with D1R plus A2AR antagonists normalizes striatal PKA activity but it does not affect motor dysfunction in R6/1 mice. In conclusion, we show that parallel alterations in dopaminergic and adenosinergic signaling in the hippoc us contribute to increase PKA activity, which in turn selectively participates in hippoc al-dependent learning and memory deficits in HD. In addition, our results point to the chronic inhibition of both D1R and A2AR as a novel therapeutic strategy to manage early cognitive impairment in this neurodegenerative disease.
Related Organisations
Related Funding Activities
No related grants have been discovered for Rodrigo Cunha.