Effects of PEA and Luteolin in an animal model of anxiety/depression in neurogenesis-dependent pathway

Rosalia Crupi, Akbar Ahmad, Emanuela Esposito, Salvatore Cuzzocrea. University of Messina, Department of Clinical and Experimental Medicine and Pharmacology, school of Medicine,Messina 98125, Italy

Mood disorders impact 7% of the world’s population, and severe forms of depression affect 2% to 5% of the US population. They are considered the fourth leading cause of disability world wide and, according to the World Health Organization, may become second only to cardiovascular diseases in the next two decades. Multiple and distinct brain regions may be responsible for the heterogeneous nature of depression. Such hypothesis has been supported by human imaging and post-mortem studies showing the involvement of different brain areas as prefrontal and cingulated cortex, hippocampus, striatum, amygdala and thalamus. Their involvement in mood and emotionality has been demonstrated by studying the neural connections between different brain areas as prefrontal cortex, amygdala and nucleus accumbens with hippocampus. The therapeutic action of currently available chemical antidepressant is realized approximately 50-60% of patients with depression and required weeks to months of chronic treatment. Many patients often are reluctant to use ‘‘synthetic agents’’ for prolonged periods of time or at all. Natural remedies may be more appealing to these patients as they are perceived as safer and commonly have a more favorable side effects profile. Among these, Palmitoylethanolamide (PEA) is a member of fatty-acid ethanolamide family. This endocannabinoids is an endogenous neuromodulator with a broad spectrum of pharmacological properties, including analgesic, anti-inflammatory, anticonvulsant and antiproliferative effects. Luteolin is a common flavonoid that exists in many types of plants such as Apium graveolens L. var. dulce, Petroselium crispum, and Capsicum annuum L. var. grossum. It is found in high amounts in parsley, thyme, peppermint, basil herb, celery and artichoke. Luteolin has various pharmacological activities such as antioxidant, anticancer action, memory-improving, and anxiolytic activities, suggesting that luteolin could penetrate easily into the brain. The aim of this study was to investigate the effects of PEA (1,10 mg/kg, i.p.) and Luteolin (10, 50 mg/kg, i.p.) in the neural development in the adult hippocampus and the behavioral changes in a depressive-like state. The antidepressant-like effect of PEA and Luteolin alone or combined, was evaluated by using a mouse model of anxiety/depressive-like behavior induced by chronic corticosterone treatment. 129 Sv/Ev male mice (N=10 for each group) were administered with corticosterone for 7 wk, and behavioral tests as novelty-suppressed feeding, open field, forced swim were performed. Cell proliferation in hippocampal dentate gyrus (DG) was investigated by 5-bromo-2- deoxyuridine and doublecortin immunohistochemistry techniques. Golgi-impregnated method was used to evaluate the changes of dendritic spines in DG neurons. The depressive-like state caused by corticosterone treatment was reversed by exogenous administration of PEA and Luteolin, alone or combined, for 2 wk; the proliferation of progenitor cells was reduced under chronic corticosterone treatment, whereas treatment with PEA and Luteolin prevented the corticosterone-induced reduction in hippocampal cell proliferation (the results were analyzed by one-way ANOVA followed by a Bonferroni post-hoc test for multiple comparison). Corticosterone-treated mice exhibited a reduced spine density, which was ameliorated by PEA administration. These findings suggest that PEA and Luteolin may play an important role in the near future in the treatment of depression.