Shaun Jordan

Aripiprazole protects cortical neurons from glutamate toxicity

Neurodegeneration is thought to be a component of schizophrenia pathology, and some antipsychotics appear to slow degenerative changes in patients. Aripiprazole, the first partial dopamine D(2) receptor agonist approved for the treatment of schizophrenia, is suggested to be neuroprotective based on non-clinical studies using transformed cell lines and in vivo stress and lesion paradigms. However, aripiprazole-induced neuroprotection has not been studied in a neuronal glutamate toxicity assay, which may model aspects of neurodegeneration occurring in schizophrenia. This study examined whether therapeutically relevant concentrations of aripiprazole protect rat embryonic cortical neurons from glutamate toxicity in biochemical and high-content imaging assays. Aripiprazole inhibited glutamate-induced neurotoxicity by 40% in a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, in contrast to risperidone and olanzapine, which had little neuroprotective activity. This neuroprotective effect of aripiprazole was not mediated by the activation of serotonin 5-HT(1A) or dopamine D(2) receptors, Akt or glycogen-synthase kinase-3β signaling (GSK-3β), or through the inhibition of poly-ADP ribose polymerase (PARP). Further experiments are required to determine the biochemical nature of aripiprazole-induced neuroprotection and whether any such activity might have clinical relevance.

In vitro functional characteristics of dopamine D2 receptor partial agonists in second and third messenger-based assays of cloned human dopamine D2Long receptor signalling

Aripiprazole, (+)terguride, OPC-4392 and (—)3-PPP have been classified as dopamine D2 receptor partial agonists based largely on their activity in second messenger-based assays of dopamine D2 receptor signalling. Nevertheless, signal transduction amplification might result in these compounds behaving as dopamine D2 receptor full agonists at a more downstream level of signalling. We compared the intrinsic activity (Emax, expressed as a percentage of the maximal effect of dopamine) of aripiprazole, (+)terguride, OPC-4392 and (—)3-PPP using second (calcium (Ca2+) mobilization) and third (extracellular signal-regulated kinase 2 (ERK2) phosphoprotein expression) messenger readouts of cloned human dopamine D2long (hD2L) receptor signalling in CHO cells. These compounds were all less potent and displayed lower intrinsic activity in the Ca2+ assay (aripiprazole = 24.3%, (+)terguride = 56.9%, OPC-4392 = 58.6% and (—)3-PPP = 75.1%), and aripiprazole (Emax = 54.5%) displayed a substantially lower intrinsic activity than (+)terguride (Emax = 92.3%), OPC-4392 (Emax = 93.1%) and (—)3-PPP (Emax = 101.1%) in the more downstream-based ERK2 phosphoprotein expression assay. These drug effects on Ca2+ mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD2L receptors, as they all were blocked by (—)raclopride, whereas (—)raclopride and other dopamine D2 receptor antagonists (haloperidol, risperidone, ziprasidone, olanzapine, clozapine and quetiapine) were inactive on their own in both assays. These data are consistent with clinical evidence that only dopamine D2 receptor partial agonists with a sufficiently low enough intrinsic activity will prove effective against the positive symptoms of schizophrenia, and also highlight the importance of using downstream-based assays in the discovery of novel D2 receptor partial agonist therapeutics.