Fingolimod ameliorates cognitive impairments in a phencyclidine-induced
rat model of schizophrenia
Abstract
Background and Purpose: Improvement of cognitive deficits in
schizophrenia remains an unmet need due to the lack of new therapies and
drugs. Recent studies have reported that fingolimod, an immunomodulatory
drug for treating multiple sclerosis, demonstrates anti-inflammatory and
neuroprotective effects in several neurological disease models. This
suggests its usefulness for ameliorating cognitive dysfunction in
schizophrenia. Herein, we assessed the efficacy profile and mechanism of
fingolimod in a rat model of phencyclidine (PCP)-induced schizophrenia.
Experimental Approach: Sprague-Dawley rats were treated with PCP for 14
days. The therapeutic effect of fingolimod on cognitive function was
assessed using the Morris water maze and fear conditioning tests.
Hippocampal neurogenesis and the expression of astrocytes and microglia
were evaluated by immunostaining. Cytokine expression was quantified
using multiplexed flow cytometry. Brain-derived neurotrophic factor
expression and phosphorylation of extracellular signal-regulated kinase
were determined using western blot analysis. Key Results: Fingolimod
attenuated cognitive deficits and restored hippocampal neurogenesis in a
dose-dependent manner in PCP-treated rats. Fingolimod treatment exerted
anti-inflammatory effects by inhibiting microglial activation and IL-6
and IL-1β pro-inflammatory cytokine expression. The underlying mechanism
involves the upregulation of brain-derived neurotrophic factor protein
expression and activation of the extracellular signal-regulated kinase
signalling pathway. Conclusion and Implications: To the best of our
knowledge, this is the first preclinical study to assess the effects of
fingolimod on cognitive function in schizophrenia models. Our results
support the role of the immune system in cognitive alterations in
schizophrenia and highlight the potential of immunomodulatory strategies
to improve cognitive deficits in schizophrenia.