Dopamine receptor D1 agonist inhibits glioblastoma via calpain­mediated ER stress and mitochondrial dysfunction.

Recent studies have reported the important roles of dopamine receptors in the early development and progression of glioblastoma (GBM). The present research aimed to explore the antineoplastic effect and intrinsic pathways of action of dopamine receptor D1 agonist SKF83959 on GBM cells. Flow cytometric analysis revealed a significant level of apoptotic cell death under SKF83959 treatment. SKF83959 administration increased intracellular calcium levels and oxidative stress through the phospholipase C/inositol trisphosphate pathway. The downstream calpains were activated and dysregulated by the increased calcium levels. The mitochondrial membrane potential­dependent staining assay revealed decreased mitochondrial transmembrane potential in GBM cells under SKF83959 treatment. The mitochondrial/cytosolic fraction and western blotting further demonstrated mitochondrial dysfunction and endoplasmic reticulum stress, followed by apoptosis. The calpain inhibitor, calpastatin, significantly reversed the increase in mitochondrial injury and endoplasmic reticulum stress and eventually ameliorated GBM cell apoptosis during SKF83959 treatment. Finally, the in vivo inhibitory efficacy of SKF83959 was verified in GBM xenograft models. In addition, immunohistochemistry and western blotting both revealed increased expression of calpains in xenograft GBM tissues. These results suggested a potential therapeutic target for human GBM treatment regarding calpain expression and activity regulation.

Hypothalamic neuropeptide Y (NPY) and the attenuation of hyperphagia in streptozotocin diabetic rats treated with dopamine D1/D2 agonists.

1. Dopamine is an appetite suppressant, while neuropeptide Y (NPY), an appetite stimulant in the brain, is reported to be involved in anorectic action induced by a combined administration of D1/D2 agonists in normal rats. In diabetic rats, however, these factors have not been studied. 2. Rats (including normal, diabetic and insulin-treated diabetic rats) were given daily injections of saline or D1/D2 agonists for 6 days. Changes in food intake and hypothalamic NPY content of these rats were assessed and compared. 3. The D1/D2 agonist-induced anorectic responses were altered in diabetic rats compared to normal rats treated similarly. Both the anorectic response on the first day of dosing and the tolerant response on the subsequent days were attenuated. 4. This alteration was independent of the neuroendocrine disturbance on feeding behavior since the basic pattern of food intake during the time course of a 24-h day/night cycle was similar in normal and diabetic rats; the decrease of food intake following drug treatment was only shown at the initial interval of 0-6 h in both groups of rats. 5. However, this alteration coincided with changes in NPY content following D1/D2 coadministration. The replacement of insulin in diabetic rats could normalize both NPY content and D1/D2 agonist-induced anorexia. 6. It is demonstrated that the response of D1/D2 agonist-induced appetite suppression is attenuated in diabetic rats compared to normal rats and that elevated hypothalamic NPY content may contribute to this alteration.

On the relative importance of D-1 vs. D-2 dopaminergic receptors in the control of audiogenic seizures in ethanol withdrawn rats.

Bromocriptine, a mixed D-1/D-2 dopaminergic receptor agonist and SKF 38393, a D-1 specific agonist were found to alleviate the incidence and intensity of audiogenic convulsions in ethanol withdrawn rats. (+) and (-)3-PPP, putative D-2 autoreceptor agonists, were without effect in the test. SCH 23390, a D-1 specific antagonist did not influence seizure intensity in ethanol withdrawn or ethanol naive animals. It is suggested that D-1 receptors may play a role in convulsive response during ethanol withdrawal.