Caspase-3 Activation in Rat Frontal Cortex Following Treatment with Typical and Atypical Antipsychotics

Abstract

In schizophrenia, studies indicate that apoptotic susceptibility in cortex may be increased. A role for apoptosis in schizophrenia could potentially contribute to post-mortem evidence of reduced cortical neuropil and neuroimaging studies showing progressive cortical gray matter loss. Interestingly, antipsychotic treatment has been associated with higher cortical levels of anti-apoptotic Bcl-2 protein in rat cortex and preliminary data has suggested a similar association in schizophrenia and bipolar disorder. To better understand the effects of antipsychotics on apoptotic regulation, rats were administered haloperidol, clozapine, quetiapine, or saline daily for 4 weeks. Multiple apoptotic markers, including Bcl-2, pro-apoptotic Bax, anti-apoptotic XIAP, and the downstream protease caspase-3 were measured in frontal cortex using Western blot. Caspase-3 activity, activated caspase-3-positive cell number, and DNA/histone fragmentation levels were also determined. Western blot showed that immunoreactivity of Bax and Bcl-2 bands were unchanged with treatment. However, mean density of the 19 kD activated caspase-3 band was 55% higher with haloperidol (po0.001), 40% higher with clozapine (po0.05), and 48% higher with quetiapine (po0.01) compared to saline control. Specific activity of caspase-3 was also increased across all treatments (po0.0001), while DNA fragmentation rates remained unchanged. These data suggest that sub-chronic antipsychotic treatment is associated with non-lethal caspase-3 activity. The findings do not support a prominent Bcl-2-mediated neuroprotective role for antipsychotics. Although the association between antipsychotic treatment and increased pro-apoptotic caspase-3 is intriguing, further study is needed to understand its potential effects. Neuropsychopharmacology (2007) 32, 95-102.

Erythropoietin Prevents Haloperidol Treatment-Induced Neuronal Apoptosis through Regulation of BDNF

“…A number of mechanisms have been suggested for HAL-induced cytotoxicity, including necrotic and apoptotic mechanisms. The increased caspase-3 activity in cultured neurons continuously exposed to HAL for 24 h is consistent with the earlier reports in rats (Ukai et al, 2004;Jarskog et al, 2007). Some studies have reported a caspase-independent pathway-mediated cell death by HAL (Wei et al, 2006;Crawford and Bowen, 2002).…”

“…The support for this hypothesis is based upon reports of significant alterations of the proteins Bcl-2 and Bax (specifically the Bax/Bcl-2 ratio) in brain regions that are known to be important to the symptomatology of the schizophrenia, such as temporal cortex (Jarskog et al, 2004). Interestingly, short-term rodent studies have indicated an upregulation of antiapoptotic markers following treatment with olanzapine and clozapine (He et al, 2004;Bai et al, 2004), but showed increased activation of caspase-3, an apoptotic marker, with chronic use of both typical and atypical antipsychotics (Jarskog et al, 2007). Other studies in rodents have indicated that typical and atypical antipsychotics can have favorable or unfavorable effects on brain levels of BDNF (and other neurotrophins such as nerve growth factor) depending on the length of treatment (Alleva et al, 1996;Parikh et al, 2004a, b, c;; reviewed by Terry and Mahadik, 2007).…”

Neuroprotective Role of Lazaroids Against Aluminium Chloride Poisoning

“…Caspase-3 represents the predominant caspase in the CNS, both in normal neurodevelopment and in neuropathological [23,24]. In the present study, chronic administration of Al could activate caspase-3 in rat brain (Fig.…”

Protective Effect of Curcumin and its Combination with Piperine (Bioavailability Enhancer) Against Haloperidol-Associated Neurotoxicity: Cellular and Neurochemical Evidence

“…Caspase-3 represents the predominant caspase in the CNS, both in normal neurodevelopmental and in neuropathological states (Jarskog et al 2007;Yuan and Yankner 2000). In the previous studies using western blotting, 40-55% increase in immunoreactivity of activated caspase-3 bands after the chronic administration of haloperidol was observed.…”