**7. The role of proinflammatory cytokines**

inflammatory cytokines in the rodent brain, such as tumor necrosis factor alpha (TNF‐α), interleukin‐1β (IL‐1β), IL‐10, interferon gamma (IFNγ), C‐reactive protein, tissue inhibitor of metalloproteinases 1 (TIMP‐1), or vascular cell adhesion molecule 1 (VCAM‐1), similar to observations in *postmortem* biopsies of schizophrenic patients. Finally, the behavioral changes have also been related to neurochemical mechanisms, with an increase in dopamine and

Any of the above mechanisms in rodents could also produce behavioral changes in the brains of other intermediate hosts, including humans. Thus, research in humans also sug‐ gests that toxoplasmosis may alter behavior, psychomotor abilities, or personality, with the corresponding clinical consequences [84]. These disorders would be more related to latent rather than acute toxoplasmosis, given that its emergence, frequently several years after pri‐ mary infection and not during the acute phase, would indicate that it results from slow and possibly accumulative changes induced by parasite activity [91–93]. The study by Horacek et al. [76] demonstrates that, in seropositive schizophrenic patients, latent parasitization is associated with a significant reduction in gray matter volume in specific brain areas (cor‐ tical regions, hippocampus, and caudate nucleus), which is not observed in seronegative

Reinforcing the relationship between the parasite and the psychiatric disease, it has been demonstrated that haloperidol, an antipsychotic drug that blocks D2 dopaminergic recep‐ tors in the mesolimbic system and often used in the symptomatic treatment of schizophrenia, inhibits the replication of tachyzoites in cell cultures *in vitro*. This effect may at least partly be due to the capacity of this drug to inhibit calcium transport, blocking cell ion channels [94]. The interaction between tachyzoites and host cells is calcium‐dependent; hence, cell inva‐ sion capacity can be inhibited by the presence of drugs that block calcium channels, such as haloperidol [95]. Experimental studies with rodents have also demonstrated that some behavioral changes caused by the infection are reverted by using the antipsychotic, and that there are fewer parasitized neurons and glial cells after the treatment; this is observed using immunohistochemical techniques [96]. It is therefore possible that its therapeutic effect can be explained in patients with schizophrenia by various mechanisms, given that on the one hand, it blocks dopamine, whose levels are often elevated in schizophrenia patients parasit‐ ized with *T. gondii* [89, 97], and on the other hand, it can inhibit parasite replication in brain cells [96]. Other antipsychotic drugs such as fluphenazine, thioridazine, trifluoperazine, or zuclopenthixol, and mood stabilizers, e.g., valproic acid, were also found to inhibit *T. gondii*

Antipsychotics are especially indicated in patients with a predominance of positive symp‐ toms and agitation (as in the acute phase of schizophrenia), which are significantly more frequent in those parasitized with *T. gondii*, as noted above. The greater effectiveness of these drugs in these situations may be due not only to their dopamine blocking effect but also to their anti‐*Toxoplasma* activity. Thus, these treatments were found to reduce anti‐*Toxoplasma* antibody levels in seropositive schizophrenic patients, indicating their antiparasitic effect [44]. These findings suggest that these drugs may possibly have a beneficial effect on schizo‐

homovanillic acid and a decrease in norepinephrine levels [73, 84, 85, 87–90].

patients.

66 Schizophrenia Treatment - The New Facets

proliferation in cell cultures [94, 98, 99].

phrenic patients parasitized with *T. gondii*.

The host response to the parasitization of glial cells and neurons involves the activation of immune system cells, including T lymphocytes (CD4+ and CD8+), B lymphocytes, NK cells, macrophages, and dendritic and glial cells. These produce a wide variety of inflammatory cytokines such as IFNγ, interleukins (IL‐1, IL‐1β, IL‐2, IL‐4, IL‐6, IL‐10, IL‐12, IL‐15, IL‐17, IL‐18, IL‐23), granulocyte macrophage colony‐stimulating factor (GM‐CSF), and/or TNFα [69, 103]. These cytokines halt protozoan proliferation and limit their replication, playing a key role in regulating the infection of host cells, thereby favoring the formation of tissue cysts and the development of the chronic latent form [20]. These and other inflammatory responses have also been reported in schizophrenia [104] and are therefore involved in brain disorders both in this disease and in *T. gondii* infection [105].

Thus, infection of brain tissue by *T. gondii* produces activation of the Jak/STAT pathway, which is recognized as an important regulatory mechanism in CNS development, function, and dis‐ ease progression [106, 107]. This pathway comprises three elements: a ligand receptor, the majority are receptors of cytokines such as IFNγ; Janus kinase (Jak) proteins associated with the receptor within the cell, which possess tyrosine‐kinase activity; and signal transducer and activator of transcription (STAT) proteins, which act as transcription factors that move toward the cell nucleus after their phosphorylation, where they bind with regulatory sequences of genes designated gamma interferon activation sites (GAS) [108]. In mammals, the Jak/STAT pathway induces the transcription of genes that participate in multiple processes, including antimicrobial activity and the production of proinflammatory cytokines [109]. Among other effects, an increase is produced in the expression of NADPH oxidase enzyme (NOX2) and inducible nitric oxide synthase (iNOS). These enzymes are responsible for the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which assist the destruc‐ tion of foreign pathogens [110, 111] but have been linked to seizures, stroke, neurodegenera‐ tive diseases, and schizophrenia [111, 112] as a consequence of their toxic effect on neurons [113]. Scientific evidence points to ROS‐mediated oxidative damage as a key pathogenic pathway involved in infection‐mediated neuropathy. According to these findings, it can be expected that a high degree of degenerated neuron degeneration and cognitive impairment is associated with the presence of *T. gondii* in the brain [111].
