1. INTRODUCTION
Schizophrenia is a severely debilitating mental disorder affecting approximately 1% of the global population. The disorder is characterized by various symptoms that can be categorised as positive symptoms (such as hallucinations and delusions), negative symptoms (such as avolition and self-neglect), and cognitive deficits (including deficits in memory and attention). Despite recent advances, the overall management of schizophrenia remains unsatisfactory. Cognitive deficits are among the symptoms of schizophrenia that are most difficult to treat. Therefore, the development of new therapies targeting cognitive dysfunction may represent the most demanding need among patients with schizophrenia.
The pathophysiology of schizophrenia is still not fully understood. However, emerging evidence suggests that the dysregulation of the immune system is linked to this disorder. Epidemiological studies have reported that patients with schizophrenia have an increased risk of autoimmune disorders (Cullen, Scarlett et al., 2018). Several genetic association studies have shown that, on average, patients with schizophrenia have an immune system that is more prone to activation (Sekar, Bialas et al., 2016; Woo, Pouget et al., 2020), which may have a detrimental effect on neurogenesis by reducing brain-derived neurotrophic factor (BDNF) expression (Lima Giacobbo, Doorduin et al., 2019). Furthermore, the loss of blood-brain barrier (BBB) integrity appears to be a common pathological finding in schizophrenia (Greene, Hanley et al., 2020), which leads to the infiltration of peripheral immune cells, culminating in neuroinflammation and oxidative stress. These disturbances are associated with disrupted glutamate homeostasis, impaired antipsychotic action, and exacerbated symptoms of schizophrenia (Pollak, Drndarski et al., 2018). These findings suggest that managing excessive pro-inflammatory processes may represent an important intervention target for this illness.
Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, is highly efficacious against multiple sclerosis (MS). It acts on the S1P1 receptor of lymphocytes and selectively retains autoreactive lymphocytes in lymph nodes, thereby reducing damage to the central nervous system (CNS) (Hla & Brinkmann, 2011). In addition to its prominent effects on lymphocyte recirculation, preclinical and clinical studies have investigated its therapeutic potential for other diseases. For example, a combination of fingolimod and alteplase attenuates reperfusion injury and improves clinical outcomes in patients with acute ischaemic stroke (Zhu, Fu et al., 2015). It has also been shown to improve depression-like behaviour in chronically stressed animal models (di Nuzzo, Orlando et al., 2015; Guo, Gan et al., 2020) and enhance learning and memory in Huntington’s disease (Miguez, García-Díaz Barriga et al., 2015) and Alzheimer’s disease models (Hemmati, Dargahi et al., 2013). As discussed above, the anti-inflammatory and neuroprotective properties of fingolimod suggest its beneficial effects in schizophrenia. Therefore, we aimed to investigate the efficacy profile and mechanism of fingolimod in a rat model of schizophrenia. To the best of our knowledge, this is the first preclinical study on the effects of fingolimod on the cognitive function in schizophrenia models.