Neuroprotective effects of olanzapine in a rat model of neurodevelopmental injury
Introduction
Nearly twenty years ago, it was hypothesized that the neuroanatomical abnormalities associated with schizophrenia might be the result of a static neurodevelopmental defect (Weinberger, 1987, Crow et al., 1989). However, it has also been reported that ventricular enlargement and volume loss in some brain structures is progressive during the course of the illness (Woods, 1998, DeLisi, 1999). In patients with childhood-onset schizophrenia, progressive losses of cortical gray matter have been observed (Thompson et al., 2001). Also, Pantelis et al. (2003), have reported progressive decreases in the volume of temporal lobe structures in young adult patients who are transitioning from having prodromal symptoms of schizophrenia to having the full form of the disorder.
Reports of progressive neuroanatomical abnormalities in subjects with schizophrenia suggest that neurodegeneration may occur during the pathogenesis of the disorder. If such observations are confirmed, treatments for schizophrenia should be assessed for their effects on neurodegenerative processes that may be relevant to schizophrenia. A variety of neurodegenerative mechanisms have been hypothesized to be involved in schizophrenia. Olney et al. have suggested that a developmental deficit of GABA interneurons could place an individual at later risk for neuronal injury via the uncontrolled activity of excitatory glutamatergic neurons (i.e., excitotoxicity) (Olney et al., 1999). Excitotoxicity is an attractive mechanism to explain neuronal injury in schizophrenia because it could be initiated and/or maintained through a variety of abnormally regulated neurotransmitter systems, including the monoamines (Farber et al., 1998) and acetylcholine (Olney et al., 1999). Also among such transmitter systems are the glucocorticoid stress hormones (Sapolsky, 2000), which could be triggered by environmental stressors, such as those (e.g., famine) that have been associated with an increased incidence of schizophrenia (Susser et al., 1998).
Another attractive theory to explain neuronal degeneration in schizophrenia is the inappropriate activation of apoptosis, a process normally associated with the elimination of redundant neurons during neurodevelopment (Johnson et al., 1995). Apoptosis occurs through a cascade of gene activation, which includes genes that both promote (i.e., BAX) (Schlesinger et al., 1997) and oppose (i.e., BCL-2) the process (Craig, 1995). In neonatal rats, we have shown that brief exposure to sublethal doses of the excitotoxin, kainic acid (KA), leads to a progressive loss of hippocampal neurons, and that apoptosis is the mechanism underlying this process (Montgomery et al., 1999). Also, the delayed neuronal loss triggered by KA administration at P7 is accompanied by an increase in neurogenesis, with some of the newly born neurons appearing to migrate to the pyramidal cell fields of the hippocampus (Dong et al., 2003). These results are consistent with observations previously made in adult animals exposed to KA (Bengzon et al., 1997). Thus, excitotoxic insults early in life, such as those that might be associated with hypoxia or other forms of perinatal trauma (Olney et al., 1999), could initiate a progressive process involving both the elimination and reorganization of neurons via apoptosis and neurogenesis.
The primary objective of this study was to determine whether treatment with olanzapine, a commonly used atypical antipsychotic drug, would inhibit the loss of hippocampal neurons and increase in hippocampal neurogenesis associated with the administration of the KA in neonatal rats (Dong et al., 2003). Olanzapine was selected for this study because of the results of a recent comparison of the long-term effects of olanzapine and haloperidol in patients with first-episode schizophrenia (Lieberman et al., 2005). In this study, treatment with haloperidol was associated with a greater rate of cortical gray matter loss than olanzapine, suggesting that the olanzapine might have had a special capacity to slow the neurodegeneration associated with schizophrenia.
Section snippets
Subjects
Sprague–Dawley dams with litters (8–12 pups per dam) were obtained from Harlan Bioproducts (Indianapolis, IN, USA). At post-natal day 7 (i.e., P7), pups were randomly assigned to one of six experimental groups. A total of 51 Spraque–Dawley rat pups were used in this study (6–10 animals per drug administration group). Procedures involving animals were conducted in accordance with institutional guidelines that are in compliance with national laws and policies.
Kainic acid administration
KA was administered to neonatal rats
Results
Mean numbers of FJB- and BrdU-labeled cells in each of the experimental groups are given in Table 1. ANOVA revealed a significant effect of drug administration on the observed density of FJB-labeled cells [F(537) = 3.77, p = 0.007)]. Between-group comparisons revealed a statistically significant reduction in the density of FJB-labeled neurons in animals administered melatonin (p = 0.02) and in animals administered the highest dose of olanzapine (12 mg/kg) (p = 0.01). Reductions in FJB labeling (∼50%)
Discussion
The results of this study suggest that olanzapine at the highest dose tested ameliorated the hippocampal neuronal loss associated with intracerebraventricular KA administration in neonatal rats. Melatonin, but not the single dose of haloperidol tested, also ameliorated hippocampal neuronal loss in this animal model of neurodevelopmental injury. The neuroprotective effects of melatonin in this model were reassuring and support the validity of this animal model for detecting the neuroprotective
Acknowledgment
This research was supported by a grant from Lilly Research Laboratories.
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