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.