The use of antioxidant compounds in the treatment of first psychotic episode: Highlights from preclinical studies

Summary

Recent evidence highlighted a pathogenetic link between redox dysregulation and the early stages of psychosis. Indeed, an increasing number of studies have pointed toward an association between oxidative stress, both at central and peripheral levels, and first psychotic episode. Moreover, basal low antioxidant capacity has been shown to directly correlate with cognitive impairment in the early onset of psychosis. In this context, the possibility to use antioxidant compounds in first psychotic episode, especially as supplementation to antipsychotic therapy, has become the focus of numerous investigations on rodents with the aim to translate data on the possible effects of antioxidant therapies to large populations of patients, with a diagnosis of the first psychotic episode. In this review, we will discuss studies, published from January 1st, 2007 to July 31st, 2017, investigating the effects of antioxidant compounds on neuropathological alterations observed in different rodent models characterized by a cluster of psychotic‐like symptoms reminiscent of what observed in human first psychotic episode. A final focus on the effective possibility to directly translate data obtained on rodents to humans will be also provided.

1. INTRODUCTION

The progression period from a healthy mental status to a psychotic state is characterized by a high vulnerability of the central nervous system (CNS) to several neurodetrimental stimuli, such as redox dysregulation and oxidative stress,1 defined as a disequilibrium between production of reactive oxygen species (ROS) and antioxidant defense.2 The most redox‐sensitive cellular subpopulation in the CNS is represented by the fast‐spiking parvalbumin interneurons, which are known to be highly affected during the complex pathological events leading to first psychotic episode.3 Indeed, for the maintenance of their physiological state, they need large amount of energetic resources, together with well‐functioning ROS‐generating and ROS‐degrading systems.4, 5, 6 Importantly, fast‐spiking parvalbumin interneurons have been described as a highly oxidative stress‐sensitive neuronal subtype, especially during the postnatal period and this also affects all the molecular pathways leading to their maturation.7, 8, 9 Oligodendrocytes are also very vulnerable to redox dysregulation, in particular during the process of myelination which requires the activation of several metabolic pathways,10, 11 resulting in an abundant ROS production accompanied by a decreased basal activity of specific antioxidant systems, such as glutathione.12 An altered redox state has been also described as a major interference for oligodendrocyte maturation and development,7, 13 because of a pathogenetic link existing between glutathione deficits in oligodendrocyte progenitors and a decreased proliferation of these cells.14 Phospholipid and polyunsaturated fatty acids (PUFA), which are known to be crucial structural elements of CNS cell membranes, have been also described as particularly vulnerable to the increased production of free radicals as well as to the decrease in antioxidant defense.15 Moreover, a significant association among negative symptoms occurring in first psychotic episode, oxidative stress, decreased PUFA content, and increased levels of lipid peroxidation has been reported.16, 17 In this context, pharmacological compounds specifically targeting an imbalanced redox state may represent promising therapeutic opportunities to prevent oxidative stress‐induced deleterious effects on cortical and hippocampal parvalbumin interneurons and oligodendrocytes. Intuitively, their benefits would be more evident if they could be administered in the very early phases of the disease, as first psychotic episodes could be clinically considered.1 In this review, studies published from January 1st, 2007 to July 31st, 2017, focused on the effects of antioxidant compounds on neuropathological alterations observed in different rodent models presenting psychotic‐like symptoms reminiscent of human first psychotic episode, will be discussed. A final comment on the real possibility to directly translate rodent data to patients will be also provided.

2. LITERATURE SEARCH METHODOLOGY

The literature source of this review consisted in PubMed publications from January 1st 2007 to July 31st 2017, found using the following combinations of keywords: first psychotic episode AND animal models; first psychotic episode AND rodent models; first psychotic episode AND mouse; first psychotic episode AND rat; first psychotic episode AND rodents; first psychotic episode AND pharmacology; first psychotic episode AND preclinical studies; oxidative stress AND first psychotic episode AND animal models; oxidative stress AND first psychotic episode AND rodent models; oxidative stress AND first psychotic episode AND mouse; oxidative stress AND first psychotic episode AND rat; oxidative stress AND first psychotic episode AND rodents; oxidative stress AND first psychotic episode AND pharmacology; oxidative stress AND first psychotic episode AND preclinical studies; antioxidant AND first psychotic episode AND rodent models; antioxidant AND first psychotic episode AND mouse; antioxidant AND first psychotic episode AND rat; antioxidant AND first psychotic episode AND rodents; antioxidant AND first psychotic episode AND pharmacology; antioxidant AND first psychotic episode AND preclinical studies.

We obtained a total of 300 publications, including 7 duplicative records which were removed from further screening. For the evaluation of the 293 remaining articles, the following inclusion criteria were considered: (i) publication language (only English language publications were included); (ii) type of publication (we only considered original research articles and reviews); (iii) subjects of the study (only studies on rodents were included); (iv) description of the used antioxidant compounds (only studies, in which administration of antioxidants has been clearly described, in terms of type of compounds and dosage, were considered). Using these criteria, we excluded 207 records and assessed for eligibility 86 full‐text articles. We further screened them excluding works (26) which: (i) did not include control groups; (ii) did not clearly report the behavioral validation of the used animal model; resulting, finally, in a total of 60 studies considered for the qualitative synthesis. The PRISMA diagram related to our literature search methodology is reported in Figure 1. The final list of the references for the writing of this review also enclosed publications cited in the Introduction paragraph and in the opening statements of the other sections of this manuscript.

Figure 1.

PRISMA flow diagram

3. ANIMAL MODELS OF FIRST PSYCHOTIC EPISODE: AN EXISTING TOOL?

An “animal model” is labeled as an “approximation of a specific human condition or disease”.18 With respect to psychosis, animal models of this mental disorder have become increasingly important, attempting to develop specific pharmacological options for this psychiatric condition. Although several reliable animal models of psychosis are actually available and largely used in neuropsychiatric research, mainly based on pharmacologic,19, 20, 21, 22, 23, 24 genetic,25, 26, 27, 28 environmental,28, 29, 30, 31, 32 and neurochemical33, 34, 35, 36 manipulations, no rodent models which specifically mimic the peculiarities of first psychotic episode in humans have been developed yet. Indeed, so far, progress in the understanding of the molecular pathways underlying this specific phase of the psychotic disorder has been based on the use of animal models only partially reproducing the neuropathological events occurring during the prenatal, perinatal, and juvenile stages of CNS development.18 In this regard, prenatal exposure to methlazoxymethanol acetate (MAM), a cell division inhibitor, has been shown to determine cortical and hippocampal atrophy, as well as NMDA receptor functioning impairment during the perinatal and juvenile ages, similar to what observed in the early phases of human psychosis.37 Prenatal models, used to induce early psychotic symptoms (such as psychostimulant‐induced increased locomotor activity or reduced prepulse inhibition) in the perinatal or juvenile periods, have been also realized by exposing a pregnant female to different environmental stressors.38 Other developmental animal models have been obtained by executing different kinds of brain lesions during the neonatal period, resulting in many of the behavioral and neuropathological alterations observed at the onset of the psychotic disorder,39 that is the reduction in parvalbumin‐positive GABAergic interneurons and the increased response to glutamatergic agonist and antagonists. A short period of isolation rearing during crucial CNS developmental stages, such as infancy and adolescence, may represent a significant stressor that causes behavioral, neurochemical, and biomolecular alterations reminiscent of what observed in patients who experienced, for the first time, psychotic symptoms, such as hyperactivity in response to novelty, reduced prepulse inhibition, as well as dysfunctions of the dopaminergic, glutamatergic, and serotonergic neurotransmissions.40, 41 These neuropathological alterations have been related to an early impairment of the hypothalamic‐pituitary‐adrenal axis, most likely mediated by an increased expression of the ROS producer enzyme NOX2 in response to social isolation rearing in the juvenile period.42 Furthermore, a short period of social isolation rearing (1 week) during a crucial period of the rat brain development, which may correspond to human infancy, has been shown to induce the loss of blood‐brain barrier integrity and permeability, triggering neuroinflammatory processes as well as alterations of the redox state.29 In rodents, administration of NMDA receptor antagonists in the very early perinatal period is known to be a reliable experimental procedure to induce brain dysfunctions and neuronal injury leading to symptoms partially reminiscent of what encountered by young patients at their first psychotic experience. In this regard, administration of ketamine during the second postnatal week (postnatal days 7, 9 and 11) has been shown to induce specific behavioral dysfunctions such as decreased attentional performance, particularly in terms of loss of the ability to develop a novel strategy, deficit in latent inhibition, reduced capacity to discriminate a novel object with respect to a familiar one, and decreased performance in the social novelty test. Behavioral impairment in this animal model has been associated to specific neuropathological alterations, such as a significant reduction in the number of cortical parvalbumin‐positive GABAergic interneurons.43 Interestingly, perinatal phencyclidine administration in rodents (postnatal days 2, 6, 9, and 12) has been reported to determine an alteration of the redox state in terms of both mitochondrial dysfunctions and decreased antioxidant defense. Indeed, increased functioning of complex I and cytochrome c oxidase, together with structural alterations and enhanced expression of apoptotic markers in specific brain regions, as well as enhanced sensitivity to restraint stress, has been described following phencyclidine treatment during the developmental period.44 Furthermore, decreased SOD1 and SOD2 expression, associated to reduced GSH content and to impaired activities of glutathione reductase and glutathione peroxidase, has been detected in the cortex and hippocampus of rodents receiving phencyclidine at postnatal days 2, 6, 9, and 12.45 A deep biomolecular approach to explain the psychotic effects and the acute neurotoxicity of phencyclidine administration during the perinatal and developmental period has been proposed in an interesting recent article, showing the involvement of a signaling pathway mediated by the expression and activation of the leucine‐rich repeat and immunoglobulin domain‐containing protein (Lingo‐1) in hippocampus.46 Accordingly, neonatal exposure to MK‐801 in rodents has been described to determine, around puberty, neuropathological alterations typical of the early phases of the psychotic disorders in humans, such as reduced cortical mRNA expression of genes encoding for metabotropic glutamatergic receptors, in particular of mGlu3.47 Another common manipulation applied to rodents to mimic symptoms reminiscent of what observed in human first psychotic episode consists in the prenatal exposure to viral or bacterial infections (influenza, toxoplasmosis, citomegalovirus, exposure to the endotoxin LPS) which induces a significant production of specific proinflammatory (ie, IL‐6, IL‐1β, TNF alpha) and anti‐inflammatory (especially IL‐10) citokynes in both the mother and pups.48 Specific nutritional deficits during the prenatal life have been also largely used to induce in animals neuropathological alterations mimicking the symptoms of first psychotic episode. In particular, it has been demonstrated that protein deprivation during pregnancy might determine several dysfunctions of brain development, including dopaminergic, serotonergic, and glutamatergic impairment, prepulse inhibition deficits, and working memory alterations later in life, especially in the postpubertal period.49, 50, 51, 52 Maternal vitamin D deficiency has been also related to an increased risk to develop early psychotic symptoms and, therefore, has been used to model the onset of the first phases of the disease in rodents, with respect to behavioral dysfunctions (regarding especially learning processes and reactions to novelties), altered neurogenesis, decreased levels of neurotrophines, morphological and functional changes in specific brain regions such as prefrontal cortex, hippocampus, and nucleus accumbens and altered expression of specific genes and proteins included in oxidative stress‐related pathways, as well as synaptic plasticity.53, 54

4. EFFECTS OF ANTIOXIDANT TREATMENTS

Emerging lines of evidence have described the effects of different antioxidant treatments in rodent models mimicking first psychotic episode.

4.1. N‐acetylcysteine

A significant number of studies are focused on the possible use of the glutathione precursor N‐acetylcysteine to prevent or reverse neuropathological alterations observed in rodent models of this disorder. In a recent study by Swanepoel and colleagues, a beneficial impact of a treatment with N‐acetylcysteine on behavioral and biomolecular alterations observed in an animal model of psychosis, obtained by rat exposure to maternal immune activation, methamphetamine administration, or a combination of both stimuli during adolescence, has been reported.55 Accordingly, it has been shown that a juvenile and adolescent treatment with this antioxidant compound prevented the loss of cortical inhibitory parvalbumin‐positive interneurons and other electrophysiological and behavioral alterations in a developmental lesional animal model.56 A beneficial impact of N‐acetylcysteine on reduced and oxidized glutathione ratio alterations, decreased expression of cortical inhibitory interneurons and impaired mitochondrial functions, and ROS production in specific brain regions has been also described in another developmental rodent model, obtained by inducing an early NMDA receptor dysfunction in male mice by ketamine administration, therefore, mimicking the first phases of the psychotic disease.57 An antioxidant treatment with this glutathione precursor has showed significant positive effects in preventing or strongly ameliorating neuropathological and behavioral alterations observed in the ketamine perinatal model of psychosis, such as decreased cognitive abilities, reduced social interactions, dysfunctions in the ability to recognize a novel object with respect to a familiar one, and reduced prepulse inhibition.58 In an elegant study of das Nueve Duarte and co‐authors, performed using mice knock‐out for the GSH‐synthesizing enzyme glutamate‐cysteine ligase modulatory subunit (GCLM‐KO), which were characterized by chronic GSH deficit associated to specific cortical neurochemical changes especially at the prepubertal age, N‐acetylcysteine, administered from gestation, has been shown to induce a normalization of all neuropathological alterations observed in GCLM‐KO mice.59 Using the same knock‐out mice, Cabuncgal and co‐authors demonstrated that a treatment with N‐acetylcisteine prevented the detrimental effects of oxidative stress occurring in crucial moments of CNS postnatal development, such as the hampered maturation of parvalbumin‐positive interneurons.13 In the same line, another research group demonstrated, using G72/G30 transgenic mice which exhibit several early psychotic‐like behavioral alterations, that N‐acetylcysteine administration in the perinatal period was able to rescue neuropathological alterations observed in these rodents, such as the decreased activity of the mitochondrial complex I, associated to consequent increase in free radical production, impaired synaptic plasticity, deficits in learning processes, as well as spatial memory acquisition and consolidation.60 In another preclinical study, N‐acetylcysteine, administered to socially isolated rats during perinatal life and from the beginning of the isolation procedure, has been shown to reverse mitochondrial, immunological, neurochemical, and behavioral deficits induced by social isolation and this effect was more significant when N‐acetylcysteine was co‐administered with clozapine.61

4.2. Apocynin

Another ROS scavenger/antioxidant compound, whose effects have been investigated in different animal models reminiscent of first psychotic episode, is apocynin, also known as acetovanillone. This compound has been also demonstrated to have an inhibitory action against NADPH oxidase, significantly preventing superoxide generation in granulocytes and resulting, finally, in beneficial effects against inflammatory processes.62 One of the first evidence on the possible effects of this compound in animal models of psychosis came from the group of Behrens. Indeed, using the ketamine model of this mental disorder, this research group demonstrated that ketamine‐induced neuropathological alterations, in terms of loss of expression of parvalbumin and GAD67 in the subpopulation of the cortical fast‐spiking inhibitory interneurons, were associated to increased superoxide production by the NADPH oxidase NOX2 enzyme and that a treatment with apocynin, decreasing the production of this free radical, prevented ketamine‐induced dysfunctions.63 However, although extremely innovative in the field, this evidence was obtained on adult animals, providing no informations about possible effects of this compound during a developmental stage of an animal model of psychosis, during which first psychotic‐like symptoms may occur. Other lines of evidence highlight the effects of this ROS scavenger in the developmental life period. Indeed, it has been demonstrated that a chronic treatment with apocynin, started at 2 weeks of age, reduced the expression of specific markers of oxidative stress and partially solved behavioral psychotic‐like symptoms in a NMDA‐R hypofunction mouse model, also exposed to social isolation.64 In the same line, we previously demonstrated that the antioxidant/NOX inhibitor apocynin, administered during the early phases of the psychotic state development induced by the procedure of the social isolation rearing, was able to fully reverse the observed behavioral alterations. Interestingly, if applied once the psychotic‐like conditions have become chronic (at the adult age), this same compound could only partially reverse the neuropathological alterations induced by social isolation.65 Furthermore, apocynin treatment in rats isolated during the developmental period and, therefore, presenting first psychotic‐like neuropathological alterations, could also stop the progression of neuroendocrine alterations induced by social isolation.42 Supporting these findings, apocynin treatment from PND 6 to PND 8 in ketamine‐treated rat pups was able to attenuate the ketamine‐induced alterations in memory and learning abilities, the increased expression of markers of oxidative stress, as well as of NOX2 enzyme, and the decreased expression of parvalbumin and GAD67 in cortical inhibitory interneurons.66

4.3. Other antioxidant compounds

Based on our literature search strategy, preclinical studies describing the use and the effects of other antioxidant compounds than N‐acetylcisteine and apocynin in rodent models of psychosis which mimics specifically first psychotic symptoms are quite limited and mainly referred to the following compounds: vitamin C, omega‐3 fatty acids, and ebselen. Evidence about these three compounds is summarized in Table 1.

Table 1.

Effects of other antioxidant compounds (vitamin C, omega‐3 fatty acid, ebselen) in rodent models of first psychotic‐like symptoms

Antioxidant compound	Animal models of psychosis/first psychotic‐like symptoms	Period of administration	Effects	References
Vitamin C	PCP mouse model	Early adultness (8‐9 wk)	Inhibition of PCP‐induced increased locomotor activity	72
	Ketamine rat model	Early adultness (8 wk)	Prevention of the ketamine‐induced hyperlocomotion and increased AChE activity	73
Omega‐3 fatty acids	NMDA receptor hypofunction (NR1KD mice)	Prenatal and perinatal life	Improvement of mice deficits in executive function but not of social interaction and PPI deficits	74
	Amphetamine‐induced rat model of schizophrenia	Adolescence	Decrease in latency time at sessions 1, 2, and 3 of the water maze task Increase in the number of alternations in the Y‐maze task Decrease in the time required to investigate a foreign rat	75
	Ketamine rat model	Youthness/Adolescence	Reduction in ketamine‐induced BDNF expression decrease Reduction in ketamine‐induced increased brain oxidative stress Prevention of ketamine‐induced inhibition of startle reflex Prevention of ketamine‐induced protein damage related to increased oxidative stress Prevention of ketamine‐induced positive and negative symptoms	76, 77, 78
	Maternal inflammation mouse model	Early life (postweaning period)	Prevention of increased N‐acetylaspartate/creatine and lower myo‐inositol/Cr in the cingulate cortex Prevention of impaired PPI Prevention of increased anxiety Prevention of GAD67 expression alterations	79
Ebselen	G72/G30 transgenic mice	Juvenile stage and adolescence	Reversal of PPI deficits	56

5. FUTURE DIRECTIONS AND CONCLUSIONS

If it should always be taken into account that each existing animal model for any kind of disease has its own strengths and weaknesses, this concept appears to be even more significant for rodent models of psychosis, in particular for those who have been developed to mimic the neuropathological events and alterations in behavior occurring in human first psychotic episode. However, psychiatric research, performed using these animal models, has largely contributed to the identification of novel pharmacological targets, finally resulting in the development of innovative therapeutic strategies. Molecules with antioxidant properties are increasingly appearing in the pharmacological scenario related to psychiatric disorders, especially to psychosis, most likely as coadiuvants to the classical antipsychotic therapies. For some of these compounds, such as N‐acetylcisteine, results obtained from preclinical studies have encouraged the scientific community to search for a possible clinical application of this molecule (alone or in combination with neuroleptics) for the treatment of subjects suffering from psychosis, with an increasing interest focused on the effects of this glutathione precursor on both the very early stages of the disease and the high‐risk state.67, 68 On the other hand, some antioxidant compounds, such as vitamin E, are commonly used as coadiuvants in the treatment of psychosis and first psychotic episode69, 70, 71 but, virtually, no data on their therapeutic efficacy in this mental disorder have been previously collected using animal models. Thus, future research directions should be addressed to the clarification of the biomolecular aspects characterizing the first psychotic episode, to maximally succeed in reproducing them in rodents and providing a “bridge” for the gap that still exists between preclinical and clinical research.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Schiavone S, Trabace L. The use of antioxidant compounds in the treatment of first psychotic episode: Highlights from preclinical studies. CNS Neurosci Ther. 2018;24:465–472. 10.1111/cns.12847