ESTABLISHING THE ROLE OF MESENCEPHALIC ASTROCYTE-DERIVED NEUROTROPHIC FACTOR (MANF) AND CEREBRAL DOPAMINE NEUROTROPHIC FACTOR (CDNF) AS THERAPEUTIC TARGETS FOR BIPOLAR DISORDER

Abstract

Bipolar disorder (BD) is a chronic mood disorder affecting ~1-2% of the global population, characterized by cycling moods of mania and depression. The exact pathogenesis of BD is unknown; however, it has been established that endoplasmic reticulum (ER) stress plays an important role. It is known that BD patients have abnormal activity and expression of ER stress proteins in several brain regions. There exists a need for a definitive diagnostic test for the early detection of BD as it is often misdiagnosed for other conditions including unipolar depression and schizophrenia. Understanding the underlying mechanisms and therapeutic targets being used by BD treatments will be helpful in establishing a diagnostic test. The current gold standard for BD treatment includes Lithium (LiCl) prescription, along with other mood stabilizers such as Valproic acid (VPA) and antipsychotics such as Olanzapine. Current therapies only relieve symptoms and are unable to stop disease progression. Neurotrophic factors (NTFs) are naturally occurring proteins that are responsible for the maintenance, differentiation, and survival of neurons. Cerebral dopamine NTF (CDNF) and Mesencephalic astrocyte-derived NTF (MANF) belong to a novel class of NTFs specific to dopaminergic neurons. This study investigated the role of CDNF and MANF as therapeutic targets for bipolar disorder in SH-SY5Y cells and Sprague Dawley rats, as well as determining the endogenous mRNA levels of CDNF and MANF in BD patients. We demonstrated that common BD mood stabilizers – LiCl and VPA – significantly increased the mRNA expression of MANF and CDNF in vitro. Additionally, we also established that these mood stabilizers alter the NTFs expression in different rat brain regions including pre-frontal cortex (PFC) and cortex. These findings suggest that BD drug treatments potentially act via NTFs in order to relieve symptoms. Thus it highlights the importance of further investigating the interaction between neurotrophic factors and bipolar disorder.