Page 79 - ITPS-8-2

INNOSC Theranostics and
Pharmacological Sciences Ketamine and SOD activity in schizophrenia

KET-treated mice suggests heightened motor activity, SOD enzymatic activity in a mouse model of schizophrenia
which is the characteristic of KET’s psychostimulant was investigated. The findings revealed that repeated KET
properties. 31,32 The enhanced locomotor activity observed administration significantly elevated SOD enzymatic
in experimental animals following the administration of activity, which may indicate an enhanced endogenous
KET is often considered a model for the positive symptoms antioxidant system resulting from an increased oxidative
of schizophrenia, including arousal and disorganized stress response. These results align with existing literature
behavior. This behavioral response may be attributed emphasizing oxidative stress as a central component of
to heightened dopaminergic activity, particularly in the schizophrenia pathology and the potential of KET to
33
nucleus accumbens, and disrupted cortical connectivity exacerbate this condition under certain dosing regimens.
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induced by the hypofunction of glutamatergic activity. Also, the observed increase in SOD enzymatic activity
8
As such, deficit in behavior that followed repeated sub- may represent a compensatory response to counteract
anesthetic doses of KET administration may be triggered elevated ROS levels induced by KET’s pharmacological
by the combined effects of direct or indirect dopamine actions. 19,35 Elevated SOD enzymatic activity may reflect
agonists and NMDA receptor antagonists. Cognitive attempts to preserve overall redox balance, although it
34
function, as inferred from the EPM performance, was also can simultaneously exacerbate the neurobiological and
impaired in the mice that received KET alone. The KET behavioral symptoms of schizophrenia. Moreover, KET’s
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group demonstrated a prolonged latency period to enter effect on NMDA receptors may lead to increase NO
the open arms (P < 0.05), which may reflect high level of generation via the NO/Ras/extracellular-regulated kinase
anxiety-induced poor task performance due to deficits 1/2 pathway, and it may also interfere with mitochondrial
37
in decision-making processes. 13,27,30 Altered exploratory function, particularly complex I activity, which further
performance and frequent entries into the closed arms as contributes to oxidative stress. 29,36 This disruption impairs
indicatives of phenotypic anxiety were observed in KET oxidative phosphorylation, increases mitochondrial NO
group during the EPM test. This finding is consistent with synthase activity, and generates superoxide radicals and
previous findings linking anxiety overload to impaired NO. 37-39 These alterations likely trigger heightened SOD
normal cognitive processes in schizophrenia models. 27,35 enzymatic activity as a compensatory response. Interestingly,
This behavioral change might be due to the disruption of preconditioning studies involving volatile anesthetics
normal glutamatergic neurotransmission caused by KET, have demonstrated that transient inhibition of complex I,
leading to impaired cognitive and memory functions. accompanied by a moderate increase in NO or superoxide
Schizophrenia pathophysiology is intricately linked radicals, activates SOD, resulting in a subsequent increase
to oxidative stress, marked by a disruption between in its activity. 38,39 However, in schizophrenia models,
the production of reactive oxygen species (ROS) and KET’s persistent effects may overwhelm this protective
antioxidant defense mechanisms. Elevated ROS activity, mechanism. 38,39 Furthermore, heightened SOD enzymatic
primarily resulting from NMDA receptor dysfunction, activity may signify increased neuroinflammation, as
disrupts glutamate homeostasis, contributing to oxidative stress activates pro-inflammatory pathways,
excitotoxicity and synaptic damage. These biochemical leading to cytokine release and neuronal damage.
3,36
alterations are closely associated with the development of Neuroinflammation exacerbates schizophrenia symptoms,
schizophrenia’s positive, negative, and cognitive symptoms. creating a cycle of oxidative damage and inflammation. 36
Among the key components of the antioxidant defense The relationship between oxidative stress and
system, SOD plays a pivotal role by converting superoxide schizophrenia symptoms was further underscored by
radicals into hydrogen peroxide (H₂O₂) and oxygen, behavioral correlations observed in the study. Elevated
thereby preventing the formation of peroxynitrite through SOD enzymatic activity may contribute to phenotypic
the interaction of nitric oxide (NO) with superoxide hyperactivity and cognitive impairments, which could be
radicals. The altered SOD enzymatic activity observed in associated with the reinforcing role of oxidative stress and
29
schizophrenia is of particular interest, as it provides insights antioxidant dysregulation in schizophrenia. These findings
into the oxidative mechanisms underlying the disorder and highlight the potential of antioxidant therapies to alleviate
the potential neuroprotective or neurotoxic implications
of SOD enzymatic activity. While heightened SOD schizophrenia-related symptoms.
enzymatic activity may reflect a compensatory mechanism Treatment with the atypical antipsychotic drug RISP
against excessive ROS production, 19,20 it also suggests an (0.5 mg/kg, intraperitoneally) provided significant
overwhelmed antioxidant defense system, which can lead therapeutic benefits in the study. RISP mitigated KET-
to persistent oxidative damage. In this study, the impact induced hyperactivity in the OFT and improved cognitive
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of repeated sub-anesthetic doses of KET administration on performance in the EPM test. Importantly, RISP

Volume 8 Issue 2 (2025) 73 doi: 10.36922/itps.6372