Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability

Abstract

The morphological effects of several neuroleptics as well as other novel and prototypic sigma ligands were examined by addition to cultures of C6 glioma cells. Sigma ligands caused loss of processes, assumption of spherical shape, and cessation of cell division. The time course and magnitude of this effect were dependent on the concentration of sigma ligand. Continued exposure to sigma compounds ultimately resulted in cell death. However, the morphological effect was reversible when sigma ligand was removed shortly after rounding. The potency of compounds to produce these effects generally correlated with binding affinity at sigma receptors of C6 glioma cell membranes labeled with [3H](+)-pentazocine. At a concentration of 100 microM, haloperidol, reduced haloperidol, fluphenazine, perphenazine, trifluoperazine, BD737, LR172, BD1008, and SH344 produced significant effects in 3–6 hr of exposure. Other compounds, such as trifluperidol, thioridazine, and (-)-butaclamol, produced significant effects by 24 hr of exposure. Despite the requirement of micromolar concentrations of ligand (some compounds were effective at 30 microM), the effect showed a remarkable specificity for compounds exhibiting sigma receptor binding affinity. Neuroleptics lacking potent sigma affinity [e.g., (-)- sulpiride, (+)-butaclamol, and clozapine] and other compounds that lack significant sigma affinity but that are agonists or antagonists at dopamine, serotonin, adrenergic, glutamate, phencyclidine, GABA, opiate, or muscarinic cholinergic receptors were without effect on cellular morphology at concentrations up to 300 microM over a period of 72 hr. Likewise, blockers and activators of Na+, K+, and Ca2+ channels and a monoamine oxidase inhibitor devoid of sigma affinity were without effect. Interestingly, 1,3-di-o-tolylguanidine (DTG), (+)-3-(3- hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP], (+)-pentazocine, (+)- cyclazocine, and other sigma-active benzomorphans and morphinans appeared inactive in up to 72 hr of culture. However, these compounds interacted synergistically with a subeffective dose of BD737 (30 microM) to produce effects usually in 6 hr or less. Also, the pH of the culture medium had a profound effect on the activity of sigma compounds. Increasing the pH from the normal range of 7.2–7.4 to pH 8.3– 8.5 shifted the dose curves (30, 100, 300 microM) for all sigma compounds to the left. Under these conditions, DTG, (+)-3-PPP, and benzomorphans produced effects in 24 hr or less.(ABSTRACT TRUNCATED AT 400 WORDS)

Does Haloperidol Have Side Effects on Histological and Stereological Structure of the Rat Kidneys?

“…[5][6][7] Similar to these findings, in our previous study, we showed that haloperidol causes liver cell injury and vasoconstriction on basilar arteries associated with chronic and highdose administration. [8,9] Stereology is a set of methods designed to concretize attentive quantitative analysis of the size, shape, and number of objects.…”

The sigma receptor ligand (+)−pentazocine prevents apoptotic retinal ganglion cell death induced in vitro by homocysteine and glutamate

“…Haloperidol is known to induce apoptosis in neuronal cells [33], thus, it is possible that in the presence of homocysteine the higher dosage of haloperidol is less neuroprotective. Haloperidol can interact with dopamine type 2 receptors [9] as well as σR1 [51,53] and has been shown to have toxic side effects [31,17]. We were interested in testing the influence of haloperiodol because it is known to interact with σR1.…”

Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood–brain barrier

“…They may be related to their direct actions as ligands on dopaminergic and serotonergic receptors (McGrath and Neifeld, 1985), or indeed other receptor classes such as sigma receptors (Vilner et al, 1995). Their neurotoxicity may result from disruptive actions on mitochondria and oxidative respiration (Dudani and Gupta, 1987) or occur via disruption of 5 cellular cholesterol metabolism (Dujovne and Zimmerman, 1969;Wiklund et al, 2010).…”