Neuroinflammation In Schizophrenia PDF 2021

JPS. Volume 10 No 1. May 2021 DOI=10.20473/jps.v10i1.20871 e-ISSN:2716-358X; p-ISSN:2355-2409 Available online at https://e-journal.unair.ac.id/JPS/index Literature Review Neuroinflammation in Schizophre...

JPS. Volume 10 No 1. May 2021 DOI=10.20473/jps.v10i1.20871 e-ISSN:2716-358X; p-ISSN:2355-2409 Available online at https://e-journal.unair.ac.id/JPS/index Literature Review Neuroinflammation in Schizophrenia Feytie Magda Mawey1,2,3, Azimatul Karimah1,2 , Erlyn Limoa4 Muhammad Nazmuddin5 1 Department of Psychiatry, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia 2 Dr. Soetomo General Hospital, Surabaya, Indonesia 3 West Papua Provincial Health Office and Hospital, West Papua, Indonesia 4 Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia 5 Department of Neurology, University Medical Center Groningen, Groningen, Netherlands Abstract Schizophrenia is a chronic debilitating mental illness. In many aspects, the ARTICLE INFO neuropathology of schizophrenia is closely associated with neuroinflammation, Received: July 21, 2020 especially microglial activation. Microglial hyperactivity, which is characterized by Revised: September 17, 2020 the predominant release of proinflammatory cytokines serves as the basis of the Accepted: September 18, 2020 neuroinflammation hypothesis in schizophrenia. The enhanced inflammatory induce Published: May 31, 2021 neuronal susceptibility to oxidative stress and trigger, glutamatergic synaptic dysregulation, especially in the mesolimbic and mesocortical pathways. Many in *) Corresponding author: vitro studies, in vivo animal evidence, post-mortem examinations, neuroimaging E-mail: evaluations with Positron Emission Tomography (PET), anti-inflammatory and [email protected] antipsychotic use converge upon the central role of microglial activation and proinflammatory cytokines as common of features schizophrenia. Keywords:. neuroinflammation schizophrenia microglial This is an open access article un- der the CC BY-SA license (https://creativecommons.org/lic enses/by-sa/4.0/) Cite this as: Mawey, F. M., Karimah, A., Limoa, E., Nazmuddin, M., “Neuroinflammation in Schizophrenia”. Jurnal Psikiatri Surabaya, vol. 10, no. 1, pp. 1-5, 2021, doi: 10.20473/jps.v10i1.20871. 1  Lolobua et al. / JPS, 10 (1): 1-5 INTRODUCTION signalling proteins in question. Large-scale GWAS studies have consistently implicated chromosome 6 in the HLA region Schizophrenia is a chronic brain disease whose underlying as the most important genome-wide association with pathophysiology remains elusive. The anatomical structure schizophrenia in GWAS studies of schizophrenia patients. and functioning of the living human brain can be studied using The immune hypothesis is based on the idea of a genetic indirect techniques, whereas direct microscopic and molecular disturbance that causes a chain reaction, increasing the risk of characterization can be achieved using only human post psychosis. The seminal paper describing 108 genetic "hits" for mortem brain tissue. Associations between psychiatric schizophrenia also found a significant correlation between genes diseases and immune system dysfunctions have been involved in immune function. As Pouget explained in his review postulated more than 100 years ago and have remained a article, this sparked interest in immune-related genes and matter of discussion ever since. While several studies since schizophrenia. then have not supported these findings, more recent studies suggest that different types of glia may play a role in the pathology of schizophrenia. The hypothesis that the MICROGLIAL ACTIVATION AND SCHIZOPHRENIA neuroimmune system plays a role in the pathogenesis of Microglia and inflammation markers different psychiatric disorders, including schizophrenia, has attained increasing interest over the past years. While glial involvement in schizophrenia has long been suspected, the extent to which it contributes to the disease's pathology has remained unknown. Microglia are a type of glial cell. Microglia are immune cells that originate in the central IMMUNE-RELATED HYPOTHESIS ON nervous system and are responsible for synaptic pruning during SCHIZOPHRENIA: EARLY CLINICAL FINDING development as well as serving as the primary mediators of nerve inflammation ,. Microglia preserve ’a silent' Immune-related theories about the etiology of phenotype in a healthy brain, in which an expanding process schizophrenia have grown in popularity, implying that spreads through the local environment to detect changes in the inflammation and autoimmunity may play a role in the environment. Microglia cells produce neurotrophic factors, pathogenesis of schizophrenia in some patients. Furthermore, provide axonal guidance, and control local cell proliferation at genetic studies have repeatedly found links between this level. Inflammatory stimuli, on the other hand, cause the schizophrenia and unique immune parameters, implying that cells to become activated, undergo morphological changes, and genetically susceptible people are more likely to develop release proinflammatory cytokines. Ramified microglia schizophrenia as a result of inflammation and immune actively search the entire brain for bacteria or debris under components influencing the brain. Increased levels of normal physiological conditions. When microglia detect a cytokines and inflammation markers have been found in danger, they rapidly change their phenotype, morphology, and people with schizophrenia, among other immune changes. In function, which is known as' microglia activation. ' To facilitate studies of patients with schizophrenia, abnormalities of the migration to the pathogen site, activated microglia take on an blood-brain barrier have been discovered, along with amoeboid morphology, with swollen cell bodies and short symptoms of central nervous system (CNS) inflammation. processes. Microglia contain both neurotoxic and Some infections that affect the mother during pregnancy are neuroprotective substances. As a result, some authors known to affect the fetus or newborn's growth or development, characterize this cell population as a two-edged sword. including the brain. Toxoplasma gondii, rubella virus, Microglial activation has been linked to the binary activation cytomegalovirus (CMV), and herpes simplex viruses, profile of peripheral monocytes, which is characterized by collectively known as the TORCH agents, are the most well- M1/M2 phenotypes. TNF-, IL-6, IL-1, ROS, and glutamate are known agents with such teratogenic properties. Neurogenesis released by M1 microglia in response to inflammation, while and neuronal migration in the developing cortex are largely M2-type microglia serve to overcome the inflammatory complete by birth in terms of neurodevelopmental processes. response and express IL-4, IL-13, IL-25, IL-1ra, insulin-like The postnatal phase is marked by rapid development, which is growth factor 1 (IGF1), BDNF, and COX1. Proinflammatory mainly characterized by glial cell proliferation and cytokines such as IL-1, IL-6, and TGF- were found to be differentiation, synapse formation, and myelination, with the elevated in patients with first episodes of psychosis and relapse human brain reaching 90–95% of its adult volume by the age schizophrenia, whereas successful treatment reduces these of two. Mednick et al. stated in their seminal article published inflammatory markers. Furthermore, the meta-analysis of 16 in 1988 that offspring of pregnant women who were exposed students published in 2018 by Wang et al reported that CSF to the 1957 influenza A virus outbreak in Helsinki had a higher levels of IL-1β, IL-6 and IL-8 were significantly elevated in risk of developing schizophrenia than offspring of women who schizophrenia patients compared with controls. were pregnant during years when the same flu strain was not present in the population. Furthermore, multiple reports Additionally, the decreased levels of the antioxidant, showed the incidence of post-influenza psychosis and glutathione (GSH), have been reported in patients with acute schizophrenia-like symptoms shortly after the 1917 influenza psychosis compared with controls. Negative symptoms have pandemic. The genome-wide association study (GWAS), been associated with low levels of GSH, and positive symptoms which established a genetic basis for schizophrenia, conducted have been positively correlated with SOD activity. a large-scale meta-analysis with 36,989 cases and 113,075 Oxidative stress occurs in new-onset as well as chronic controls, resulting in the identification of 100 schizophrenia- schizophrenia. Oxidative stress markers are found in peripheral related loci, indicating that genes in the calcium signalling blood, neutrophils, red blood cells, platelets, cerebrospinal fluid pathway are crucial. CACNA1C and CACNA1 are the (CSF), and brain tissue. 2 Jurnal Psikiatri Surabaya  JPS. Volume 13 No 1. May 2021 / Neuroinflammation in Schizophrenia Bodies of neuroimaging studies support the possible therapy for schizophrenic patients is most effective in the early contribution of enhanced microglial activity in schizophrenia stages of the disorder. Studies that have found little benefit to pathology. Neuroinflammation can be measured using PET this hypothesis back up this theory. Another anti-inflammatory with ligands for translator protein (PK-11195), which is highly agent, acetylsalicylic acid (ASA), has also been shown to help expressed by activated microglia t and thus, a sensitive people with schizophrenia. A meta-analysis of five double-blind measure for estivating microglial activation in the CNS. trials of nonsteroidal anti-inflammatory drugs in schizophrenia Studies have found greater binding of PK11195 in (four celecoxib studies and one ASA study) showed that the schizophrenia. Furthermore, another PET study using medication had a beneficial effect on overall symptoms as well DAA1106 as the measure of pro inflammatory microglial as positive and negative symptoms (four celecoxib studies and activation, indicated that the radiotracer binding correlated one ASA study). A meta-analysis of eight studies (six on with the duration of the disease. However, it should be celecoxib and two on ASA) found that patients with first mentioned that the results of PET studies in schizophrenia are psychotic episodes and stable chronic schizophrenia benefited inconsistent ,. Stages of schizophrenia (e.g., first vs. the most from these interventions. chronic episodes), drugs, and other interfering factors may all play a role in the contradictory results , , CLINICAL IMPLICATIONS OF NEUROINFLAMMATION IN SCHIZOPHRENIA Enhanced neuroinflammation triggers glutamate and The role of glutamate dysregulation in mesolimbic systems dopamine dysregulation impact positive symptoms. Kindling, also known as "sensitization," is a mechanism in Positive signs of schizophrenia are linked to dopamine which an initial immune response to a stimulus, such as stress hyperactivity in these downstream mesolimbic dopamine or infection, decreases the response threshold for subsequent neurons. However, disconnectivity in upstream glutamate responses to the same stimulus, resulting in a greater immune neurons, i.e. weakened and hypofunctional glutamate internal response or cytokine release than when the stimulus was first GABA innervation nerves containing GABA receptors on presented. Animal studies were used to investigate the NMDA receptors containing synapses, is thought to be the cause processes underlying stress and inflammation susceptibility of this downstream impact. It's also conceivable that, through a models, and stress was consistently linked to higher levels of four-neuron circuit, the disconnectivity of upstream glutamate proinflammatory cytokines , neurons in the hippocampus leads to downstream mesolimbic Psychotic episodes in schizophrenia are associated with dopamine hyperactivity. To control dopamine, glutamate inflammatory processes connected to the hypothalamic- brainstem projections interact with mesolimbic dopamine pituitary stress-inflammatory pathways, according to this pathways in the ventral tegmental region (VTA) The cortical theory. Microglia and astrocytes become activated as a result brainstem pathway to VTA will be overactive if the NMDA of this. Interestingly, the latter is linked to increased kynurenic receptor on cortical GABA inter neurones is hypoactive, acid (KYNA) development in the cerebrospinal fluid and resulting in excessive glutamate release in VTA. The activation of the kynurenine pathway (CSF). The only mesolimbic dopamine pathway would be overstimulated, recognized natural N-methyl-D-aspartate (NMDA) receptor resulting in excessive dopamine release in the nucleus antagonist involved in inflammatory processes is this accumbens. The ventral hippocampus's hypofunctional NMDA metabolite. Because of KYNA's antagonistic impact on the receptors at glutamatergic synapses can also lead to mesolimbic glutamatergic system, dopaminergic neurons become dopamine hyperactivity. Glutamate released in the ventral dysregulated. hippocampus binds to the NMDA receptor on GABAergic Other additional effects of neuroinflammatory interneurons, causing GABA release to be stimulated. GABA hyperactivation are the enhanced neural oxidative stress and binds to glutamate receptors on glutamate pyramidal neurons the activation of arachidonic acid pathways. The oxidative that project to the nucleus accumbens, inhibiting glutamate radicals are triggered by the activation of NMDA receptors release. The absence of glutamate in the nucleus accumbens through glutamate. Glutamate is actively taken up into allows normal activation of the globus pallidus-projected astrocytes and converted into glutamine. Changes in glutamine GABAergic neurons, which in turn allows normal activation of increase calcium entry into neurons, which can contribute to the GABAergic neurons in the ventral tegmental region (VTA). excitotoxicity and alter nerve transmission via NMDA As a consequence, the dopamine mesolimbic pathway from the antagonism.The glutamatergic imbalance leads further to ROS VTA to the nucleus accumbens is activated normally. The and RNS, leading to DNA, protein and lipid breakdown, in glutamatergic pathway to the nucleus accumbens would be situations where oxidative defences are already vulnerable overactive if the NMDA receptors on the ventral hippocampal. GABA interneurones are hypoactive, resulting in excessive glutamate release in the nucleus accumbens. Overstimulation of GABAergic neurons projecting to the globus pallidus will result, Anti-inflammatory therapy in schizophrenia which will prevent GABA release from the globus pallidus into the VTA. The mesolimbic dopamine pathway would be The discovery that anti-inflammatory medications may disinhibited, resulting in excessive dopamine release in the help people with schizophrenia may be the most compelling nucleus accumbens. evidence yet that inflammation plays a role in the disease. Inhibitors of cyclooxygenase (COX) are the subject of this overview. Celecoxib, a COX-2 inhibitor, is the most studied The role of glutamate dysregulation in mesocortical systems COX inhibitor. Patients with a disease period of fewer than impact negative symptoms two years gained from the addition of celecoxib, whereas those with a longer disease duration did not vary from the placebo Negative signs of schizophrenia are linked to dopamine community. These results indicate that COX-2 inhibitor hyperactivity in these downstream mesocortical dopamine neurons. A pyramidal interneuron connects the glutamate May 2021 3  Lolobua et al. / JPS, 10 (1): 1-5 brainstem projection to the mesocortical dopamine pathway in Schizophrenia, 44 th edit. Cambridge UK: “Springer Nature the ventral tegmental region (VTA), controlling dopamine Switzerland AG 2020, 2020. release in the prefrontal cortex. The cortical brainstem P. F. Buckley, “Neuroinflammation and Schizophrenia,” pathway to VTA will be overactive if the NMDA receptor on Curr. Psychiatry Rep., vol. 21, no. 8, pp. 19–21, 2019, doi: the cortical GABA inter neurone is hypoactive, resulting in 10.1007/s11920-019-1050-z. excessive glutamate release in VTA. This will result in overstimulation of brainstem pyramidal neurons, which will N. Müller, E. Weidinger, B. Leitner, and M. J. Schwarz, then suppress mesocortical dopamine neurons. It inhibits the “The role of inflammation in schizophrenia,” Front. Neurosci., production of dopamine in the prefrontal cortex, and is thought vol. 9, no. OCT, 2015, doi: 10.3389/fnins.2015.00372. to be the biological basis for psychotic symptoms. A. G. Dietz, S. A. Goldman, and M. Nedergaard, “Glial cells in schizophrenia: a unified hypothesis,” The Lancet Psychiatry, vol. 7, no. 3, pp. 272–281, 2020, doi: Neuroinflammation causes cognitive impairment in 10.1016/S2215-0366(19)30302-5. schizophrenia L. J. De Picker, M. Morrens, S. A. Chance, and D. Boche, Neuroinflammation can have indirect biological effects on “Microglia and brain plasticity in acute psychosis and cognition by hippocampus neurotrophic factor modulation. schizophrenia illness course: A meta-review,” Front. Psychiatry, While further research into the relationship between vol. 8, no. NOV, pp. 1–14, 2017, doi: 10.3389/fpsyt.2017.00238. inflammation, cognition, and neurotrophic factors is needed, there is evidence that cytokines can influence BDNF levels and L. E. Laskaris et al., “Microglial activation and behaviour. In particular, proinflammatory cytokines such as progressive brain changes in schizophrenia,” Br. J. Pharmacol., TNF-α and IL-1β decrease BDNF expression, leading to the vol. 173, no. 4, pp. 666–680, 2016, doi: 10.1111/bph.13364. inhibition of long-term potentiation as the underlying I. López-González, R. Pinacho, È. Vila, A. Escanilla, I. mechanism of memory formation in the hippocampus. Ferrer, and B. Ramos, “Neuroinflammation in the dorsolateral Additionally, the crosstalk between M1 microglial and prefrontal cortex in elderly chronic schizophrenia,” Eur. hippocampal neurons via CX3C receptor 1 is known to prevent Neuropsychopharmacol., vol. 29, no. 3, pp. 384–396, 2019, doi: hippocampal neurogenesis. The proinflammatory 10.1016/j.euroneuro.2018.12.011. microglial activity also enhances kynurenine by inhibiting indoleamine 2,3-dioxygenase (IDO), the key enzyme of P. S. Bloomfield et al., “Microglial activity in people at tryptophan/kynurenine metabolism –. Finally, the ultra high risk of psychosis and in schizophrenia: An enhanced inflammatory state in the brain, induces the [11C]PBR28 PET brain imaging study,” Am. J. Psychiatry, vol. production of all the hormones produced along the 173, no. 1, pp. 44–52, 2016, doi: hypothalamic-pituitary-adrenal (HPA) axis, which 10.1176/appi.ajp.2015.14101358. subsequently leads to glutamatergic-dopaminergic imbalance T. R. Marques et al., “Neuroinflammation in to cognitive alteration in schizophrenia ,. schizophrenia: meta-analysis of in vivo microglial imaging studies,” Psychol. Med., vol. 49, no. 13, pp. 2186–2196, 2019, doi: 10.1017/S0033291718003057. SUMMARY M. Norbert, “Inflammation in Schizophrenia : Convergent lines of epidemiological genetic and clinical Pathogenetic Aspects and Therapeutic Considerations,” no. evidence indicate that the inflammatory pathway is altered in April, pp. 1–10, 2018, doi: 10.1093/schbul/sby024. schizophrenia. Neuroinflammation has been suggested as a potential mechanism underlying these brain changes, with C. C. Watkins and S. Ramsay, “Clinical studies of evidence of increased density and activation of microglia, the neuroin fl ammatory mechanisms in schizophrenia,” 2015, doi: immune cells that inhabit the brain. Controversial evidence 10.1016/j.schres.2015.07.018. results in increased density of microglial cells, which act as S. Najjar, S. Pahlajani, V. De Sanctis, J. N. H. Stern, A. main cells for immune defense in the brain. However, there are Najjar, and D. Chong, “Neurovascular Unit Dysfunction and higher numbers of microglial cells in psychotic patients who Blood–Brain Barrier Hyperpermeability Contribute to commit suicide, and several studies report changes in the Schizophrenia Neurobiology: A Theoretical Integration of expression of surface markers associated with microglia in Clinical and Experimental Evidence,” Front. Psychiatry, vol. 8, schizophrenia. This suggests that no. May, 2017, doi: 10.3389/fpsyt.2017.00083. immunological/inflammatory factors may be relevant to the B. Pedraz-Petrozzi, O. Elyamany, C. Rummel, and C. pathophysiology of psychosis. Mulert, “Effects of inflammation on the kynurenine pathway in The positive effect of anti-inflammatory medications in schizophrenia - A systematic review,” J. Neuroinflammation, schizophrenia may provide the most compelling evidence that vol. 17, no. 1, pp. 1–17, 2020, doi: 10.1186/s12974-020-1721-z. inflammation is involved in schizophrenia. The most studied “Psychosis and Schizophrenia,” in Stahl’s Essential COX inhibitor is the COX-2 inhibitor celecoxib psychopharmacology, 2013. S. A. Kusuma and Y. Setiawati, “LITERATURE REFERENCES REVIEW : COGNITIVE DYSFUNCTION IN M. D. Benjamin J. Sadock, M.D. Virginia A. Sadock, SCHIZOPHRENIA,” vol. 9. M.D. Pedro Ruiz, Ed., “Schizophrenia and other Psychotic J. Kindler et al., “Dysregulation of kynurenine Disorder,” in Kaplan & Sadocks’s Comprehensive Textbook of metabolism is related to proinflammatory cytokines, attention, Psychiatry, Tenth., New York: Wolters Kluwer, 2017, p. and prefrontal cortex volume in schizophrenia,” Mol. Psychiatry, Schizophrenia and other Psychotic Disorder. vol. 25, no. 11, pp. 2860–2872, 2020, doi: 10.1038/s41380-019- et al Khandaker GM., Neuroinflammation and 0401-9. 4 Jurnal Psikiatri Surabaya  JPS. Volume 13 No 1. May 2021 / Neuroinflammation in Schizophrenia H. Noyan et al., “Association of the kynurenine pathway metabolites with clinical, cognitive features and IL- 1β levels in patients with schizophrenia spectrum disorder and their siblings,” Schizophr. Res., vol. 229, pp. 27–37, 2021, doi: 10.1016/j.schres.2021.01.014. E. Nanou and W. A. Catterall, “Calcium Channels, Synaptic Plasticity, and Neuropsychiatric Disease,” Neuron, vol. 98, no. 3, pp. 466–481, 2018, doi: 10.1016/j.neuron.2018.03.017. C. Fourrier, G. Singhal, and B. T. Baune, “Neuroin fl ammation and cognition across psychiatric conditions,” pp. 1– 12, 2019, doi: 10.1017/S1092852918001499. May 2021 5