Aspirin (acetylsalicylic acid) is a commonly prescribed drug with a wide pharmacological spectrum. At concentrations compatible with amounts in plasma during chronic anti-inflammatory therapy, acetylsalicylic acid and its metabolite sodium salicylate were found to be protective against neurotoxicity elicited by the excitatory amino acid glutamate in rat primary neuronal cultures and hippocampal slices. The site of action of the drugs appeared to be downstream of glutamate receptors and to involve specific inhibition of glutamate-mediated induction of nuclear factor kappa B. These results may contribute to the emerging theme of anti-inflammatory drugs and neurodegeneration.

The pre-synaptic protein α-synuclein is the main component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinson’s disease and dementia with Lewy bodies. Mutations in the α-synuclein gene cause familial forms of Parkinson’s disease and dementia with Lewy bodies. We previously described a transgenic mouse line expressing truncated human α-synuclein(1-120) that develops α-synuclein aggregates, striatal dopamine deficiency and reduced locomotion, similar to Parkinson’s disease. We now show that in the striatum of these mice, as in Parkinson’s disease, synaptic accumulation of α-synuclein is accompanied by an age-dependent redistribution of the synaptic SNARE proteins SNAP-25, syntaxin-1 and synaptobrevin-2, as well as by an age-dependent reduction in dopamine release. Furthermore, the release of FM1-43 dye from PC12 cells expressing either human full-length α-synuclein(1–140) or truncated α-synuclein(1-120) was reduced. These findings reveal a novel gain of toxic function of α-synuclein at the synapse, which may be an early event in the pathogenesis of Parkinson’s disease.

Activation of dopamine D₁ receptors is critical for the generation of glutamate-induced long-term potentiation at corticostriatal synapses. In this study, we report that, in striatal neurons, D₁ receptors are co-localized with N-methyl-d-aspartate (NMDA) receptors in the postsynaptic density and that they co-immunoprecipitate with NMDA receptor subunits from postsynaptic density preparations. Using modified bioluminescence resonance energy transfer, we demonstrate that D₁ and NMDA receptor clustering reflects the existence of direct interactions. The tagged D₁ receptor and NR1 subunit cotransfected in COS-7 cells generated a significant bioluminescence resonance energy transfer signal that was insensitive to agonist stimulation and that did not change in the presence of the NR2B subunit, suggesting that the D₁ receptor constitutively and selectively interacts with the NR1 subunit of the NMDA channel. Oligomerization with the NR1 subunit substantially modified D₁ receptor trafficking. In individually transfected HEK293 cells, NR1 was localized in the endoplasmic reticulum, whereas the D₁ receptor was targeted to the plasma membrane. In cotransfected cells, both the D₁ receptor and NR1 subunit were retained in cytoplasmic compartments. In the presence of the NR2B subunit, the NR1-D₁ receptor complex was translocated to the plasma membrane. These data suggest that D₁ and NMDA receptors are assembled within intracellular compartments as constitutive heteromeric complexes that are delivered to functional sites. Coexpression with NR1 and NR2B subunits also abolished agonist-induced D₁ receptor cytoplasmic sequestration, indicating that oligomerization with the NMDA receptor could represent a novel regulatory mechanism modulating D₁ receptor desensitization and cellular trafficking.