Differential effects of antipsychotics on the development of rat oligodendrocyte precursor cells exposed to cuprizone
Abstract
Cuprizone (CPZ) is a copper-chelating agent and has been shown to induce white matter damage in mice and rats. The compromised white matter and oligodendrocytes (OLs) respond to some antipsychotics in vivo. However, little is known about the effects of antipsychotics on cultured OLs in the presence of CPZ. The aim of this study was to examine effects of some antipsychotics on developing OLs in the presence of CPZ. Oligodendrocyte progenitor cells (OPCs) were prepared from rat embryos; OLs at different developing stages were labeled with specific antibodies; levels of CNP and MBP proteins in mature OLs were
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The CPZ-fed mice showed poor motor coordination in a rota-rod analysis [14] and a murine motor test [22]. In the 3rd and 4th weeks after consuming CPZ-containing diet, mice exhibited an increase in CNS activity. Moreover, mice displayed prepulse inhibition deficits during the 2nd and 3rd weeks of CPZ exposure period and showed less social interaction after CPZ exposure for 4–6 weeks [25, 44]. The CPZ-fed mice also showed spatial working memory impairment [25, 39, 44]. CPZ-induced demyelination and behavioral changes were also seen in rats [16, 18, 34]. These previous studies reminded us of an emerging hypothesis that oligodendroglial dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome [10].
In efforts to test the OL deficit hypothesis of schizophrenia, we examined the effects of some existing antipsychotic drugs on the CPZ-induced white matter damage and behavioral changes in C57BL/6 mice. We found that the CPZ-induced demyelination and myelin breakdown as well as the concurrent neuropathological changes in the mice were ameliorated by the antipsychotic quetiapine [QUE; 41, 50]. But, the other antipsychotics (clozapine, CLZ and haloperidol, HAL) showed different effects on the CPZ-induced changes [42]. Also, these antipsychotic drugs differentially affected the recovery of CPZ-induced changes after removal of
The resulting high dopamine levels are responsible for the hallucination, dissociation and psychosis within reactions to PCP.
Physiological Changes Due to Risperdal Hallucinations, delusions, paranoia, psychosis and thought disorder are all symptoms of Schizophrenia and people who suffer from these symptoms seek the treatment of atypical anti-psychotic medications. Those medicines include Risperidone (Risperdal), Clozapine (Clozaril) , Ziprasidone (Geodon) and Quetiapine(Seroquel). The purpose of these medications is to alleviate symptoms of Schizophrenia and lessen the chances of a recurrence. The basic function of Atypical Antipsychotics is to reduce the effects of blockage in the dopamine receptors and serotonin and allow communication between nerve cells. Dopamine is thought to be relevant in Schizophrenic symptoms and
Genetics can cause differences in brain chemistry and biochemistry may be important in the development and maintenance of schizophrenia. The dopamine
It was hypothesized that Cup 3 with the soda water would have the greatest amount of chemical weathering because of the soda water having the highest pH balance at the beginning of the experiment. Seeing that is was the most acidic; would create the most results. After conducting the experiment, the hypothesis was incorrect. After completing the experiment, the results for the soda water ended up being the cup with the second lowest change in mass of the rock. The rocks beginning weight began at 11.7g and ending at 11.6g., resulting in a change of -.01g. The rock that was in Cup 1 with the 50% vinegar solution had the greatest change in mass. The rock weighing at 8.3g, and then weathering down to 7.0g. Cup 1 had a total change of
The brain is composed of mostly grey and white matter. Grey matter contains most of the neuronal connections for the brain. It can be found on the outer surface of the cerebellum and around the spinal cord. “Observations have been made of reductions in the size and total neuron numbers, but not in neuronal density,” (Höistad, 2009, p. 3). This is an outstanding discovery when analyzing schizophrenia. White matter contains many neurons as well. Researchers pay close attention to these neurons and the myelination of the axons. “Interstitial white matter neurons have been found to be increased in prefrontal white matter and temporal white matter in subjects with schizophrenia, supporting further the presence of a neurodevelopmental abnormality in schizophrenia,” (Höistad, 2009, p. 3). This means that they white matter neurons never became myelinated and mature in parts of the brain. Problems like these can mess with the connections in the brain between neurons. Research like this highlight schizophrenia as being a developmental disorder of the brian, but more research is being done including other areas as well. “The pruning of axonal connections during brain development and maturation may be necessary for adequate formation of appropriate neuronal circuits,” (Höistad, 2009, p.
(2) However, there are some problems with this evidense. Amphetamines only mimic the positive symptoms of schizophrenia. They do not produce any of the negative symptoms. Likewise, anti-psychotic drugs are only affective on the positive symptoms of the disease. There is still some evidense that schizophrenics do posess higher levels of dopamine, however, these increases are only found in the striatum of the brain (7). The striatum is a region of the brain that receives its inputs from and outputs to the cortex. Injury to the striatum results in problems with intiation and control of motor behavior. (9) Also, there is evidence that the prefrontal cortex produces lower levels of dopamine. (4) The prefrontal cortex is involved in the organization and coordination of information to and from the cortex. (7)
The vast majority of medications currently in the marketplace or under development to treat schizophrenia/psychosis focus on dopamine in one way or another. Most of the medications that are currently used to treat this condition affect dopamine in a direct way. These drugs specifically target this substance because historically, psychosis has been linked to unusually high levels of dopamine in the part of the brain that is known as the stratum (Nauert, 2010). Moreover, there is a fair amount of research that indicates there is a direct correlation between levels of glutamate, which is another substance the brain produces and is found in the hippocampus, and dopamine in individuals who eventually develop schizophrenia.
Cognitive impairment (CI) is observed in the vast majority of individuals with schizophrenia and has long been identified as a principal contributor to functional deficits. To date, pro-cognitive pharmacologic therapies have been largely unsuccessful in addressing CI and as such, psychosocial treatments for cognitive enhancement in schizophrenia are increasingly important. Cognitive remediation (CR) training is a set of methods that employ principles of neuroplasticity for cognitive
While the main action of typical antipsychotics is on the D2 receptor, atypical antipsychotics show enhanced activity at 5-HT receptors with a low affinity for D2 receptors (Divac et al., 2014). Atypical antipsychotics are more effective in reducing cognitive and negative symptoms and result in fewer EPS than the typical antipsychotics (Davis, Chen, & Glick, 2003). The high binding affinity
A study done by Christina Dalman found that “central nervous system disturbances can arise through several mechanisms” (235). The three main etiological mechanisms that they focused on were malnutrition during fetal life, extreme prematurity, and hypoxia or ischemia. The results of this study indicated that “preeclampsia remained the strongest risk factor by increasing the risk for schizophrenia by 2 to 2.5 times” (Marenco and Weinberger 503). Reduced blood supply to the fetus and reduced nutrition resulted in a higher risk of preeclampsia resulting in a higher risk of
Over the years, experiments have produced evidence to suggest that dopamine plays a role in the development of Schizophrenia (Howes, McCutcheon, & Stone, 2015). Dopamine is a neurotransmitter that is produced in the substantia nigra and ventral tegmental regions of the brain. The belief that dopamine was involved in Schizophrenia arose after multiple studies performed with compounds produced an increase in extracellular concentrations of dopamine (Lieberman, Kane, & Alvir, 1987). The patients that were administered these compounds had similar symptoms to those observed from patients who were diagnosed with Schizophrenia (Lieberman et al., 1987).
The most common explanation for mental disorders is a chemical imbalance in the brain, but how and why these imbalances happen is not yet known. Since a complex web of nutrients, such as zinc, vitamin B6, and vitamin B12, are the building blocks that the brain needs to make the
This can be shown through the many advertisements on TV for medication that is made for these disorders, however what these advertisements don't focus on is the after effects. Many do say them towards the end in a lower undetectable tone, so you do not adhere to their warning. A study in the Archives of General Psychiatry, they examined the relationship between long-term antipsychotic treatment and brain volume in first-episode schizophrenia patients, they found that found that gray matter volumes of all brain regions except for the cerebellum decreased over time. This is important because gray matter is the darker tissue of the brain and spinal cord, consisting mainly of nerve cell bodies and branching dendrites. This study may open the doors to studies how other drugs affect your brain like
Omega-3 fatty acid depletion has been proposed mechanism for ERG abnormalities in schizophrenic patients. Specifically, docosohexaenoic acid (DHA) is found in high concentrations in the central nervous system, with the highest levels found in the outer segments of photoreceptors in the retina. There have been reports of significantly lower levels of essential fatty acids in the red blood cells of schizophrenic patients treated with neuroleptics and increased breakdown of membrane phospholipids in drug naïve schizophrenic patients using magnetic resonance spectroscopy. Previous studies have demonstrated reduced brain omega-3 fatty acid levels in schizophrenia, with demonstrated abnormalities in ERG. More recent research has investigated the possible relationship between omega-3 fatty acids and the dopamine hypothesis (which is discussed in more detail below). Quantitative changes in n-3 fatty acids have been shown to have quantitative effects in dopamine concentration and amount of
Oligodendrocytes are the most vulnerable brain cells to oxidative stress due to its high metabolic demand for synthesizing myelin sheaths (Ichinose et al., 2014), and relatively low levels of antioxidants (Lassmann and Van Horssen, 2011). Accumulating evidence suggests that oxidative stress plays a major role in the pathogenesis of MS. In the present study, cuprizone diet significantly increased brain TBARS level and decreased GSH content. These results are consistent with previous reports which reported that reactive oxygen species (ROS), produced as a consequence of alteration in the mitochondrial electron transport chain, have been implicated as mediators of demyelination and axonal damage in both MS and its animal models (Ghaiad et al., 2017; Kashani et al., 2014). On the other hand, treatment with linagliptin showed significant reduction in TBARS level and increase in GSH