Antidepressant-like effects of β-caryophyllene on restraint plus stress-induced depression
Eun-Sang Hwang, Hyun-Bum Kim, Seok Lee, Min-Jeong Kim, Kwan-Joong Kim,
Gaeul Han, Se-Young Han, Eun-A Lee, Jeong-Hee Yoon, Dae-Ok Kim, Sungho Maeng,
Behavioural Brain Research, 2020, 380, 112439
doi : 10.1016/j.bbr.2019.112439
A B S T R A C T
Chronic stress is depressogenic by altering neurotrophic and neuroinflammatory environments of the organism. The endocannabinoid system controls cognitive and emotional responses related with stress through the interaction with endocannabinoid receptors. β-Caryophyllene (BCP) is a CB2 agonist that exhibited anti-inflammatory, analgesic effects but minimal psychoactive effects.
To test if BCP exhibits antidepressant-like action, animals were chronically restrained with additional stressors for 28 days, and BCP (25, 50, 100 mg/kg) was intraperitoneally injected once a day during the stress inflicting period. Then despair related behaviors and hippocampal expression of neurotrophic, inflammatory and cannabinoid receptor levels were measured. To test the effect of BCP on long-term depression, field potentials were measured during the application of lipopolysaccharide and low frequency stimulation.
In the tail suspension test and forced swim test, chronic stress-induced despair behaviors were reduced by BCP. Also BCP improved the stress-related changes in the hippocampal expression of COX-2, BDNF, and CB2 receptor expression. In organotypic hippocampal slices, BCP reduced the lipopolysaccharide induced intensification of the long-term depression. In conclusion, BCP improved chronic stress related behavioral and biochemical changes. These results suggest that BCP may be effective in treating depression and stress related mental illnesses.
Keywords : Depression, β-Caryophyllene, Restraint-stress, Cannabinoid 2 receptor
Major depression is a common disorder characterized by disrupted mood, anorexia, and loss of interest in enjoyable activities [1,2]. The worldwide number of people living with depression reached 322 million, and the incidence is continuously rising . Despite decades of research, the etiology and pathophysiology of depression remains largely unknown, due to the involvement of multiple brain circuits which makes the pathophysiology very complex .
Chronic and uncontrolled stress are common causes of depression, which alter the nervous, endocrine, and immune system . These changes evoke the cognitive symptoms and physiologic changes of depression such as feeling melancholy, lack of motivation, and helplessness . Postmortem brains of major depressive disorder patients have decreased glial cell density and reduced neuron size in the stress-sensitive subcortical and cortical regions [6,7]. These microstructural changes are related with attention deficit, anxiety, and cognitive impairment . Also changes in lipid-derived neurotransmitters, such as endocannabinoids (eCBs), were found in the brains of animal models of depression .
The endocannabinoid system regulate many cognitive and emotional responses related with stress and anxiety [9,10]. The endocannabinoid system consists of eCBs, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), enzymes that synthesize and degrade the eCBs, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol (MAG), and the cannabinoid receptors CB1 and CB2 . Recently, evidences have emerged regarding the involvement of the eCB system in the pathogenesis of depression. CB1 receptor signaling contributes to depressive-like phenotypes by modulating neurotransmitters in noradrenergic, serotonergic, dopaminergic, GABAergic, and glutamatergic synapses and inhibit the stress-response axis . CB2 receptors were known to express only on peripheral tissues such as lymphocytes, macrophages, and monocytes but recently was discovered
in the brain, such as the cerebellum and hippocampus and involved in mood regulation . Hippocampal expression of CB2 receptor was decreased in a stress-induced animal models of depression [13,14]. Antidepressants increased the expression of CB2 receptor in the cortex and hippocampus . Additionally, cannabidiol (CBD), a phytocannabinoid with weak agonist/inverse agonistic properties to CB1 and CB2 receptor, showed a dose-dependent antidepressant effect in rodents [16–18].
β-Caryophyllene (BCP) is a bicyclic sesquiterpene found in plant foods such as oregano, cinnamon, pepper, and cloves . BCP is one of the main substances found in the essential oils of Ocimum gratissimum, Croton campestris, Murraya paniculata L., and Cannabis sativa . In previous studies, BCP was shown to have several pharmacological activities such as neuroprotective, anticonvulsant, activities [19,21,22]. CB2 receptors exist in the brain and are inducible under neuroinflammatory conditions, and in contrast to CB1 receptor agonists, CB2 receptor agonist do not cause psychoactive effects . It has also shown therapeutic benefits toward neuropathic pain, ulcerative colitis, and anxiety [24–26]. As a selective CB2 receptor agonist, BCP has anti-inflammatory and analgesic effects with minimal psychoactive effects [27–29]. Furthermore, BCP treatment has been reported to have an anti-depressant like effect in mouse through forced swimming test (FST) and tail suspension test (TST) . As inflammatory responses are related with depression, and inducible properties of CB2 receptor in response to inflammation, CB2 agonist is suggested to attenuate the depressogenic effect of neuroinflammation .
Based on these finding, we tested if BCP can exert antidepressant effects in relation with suppression of inflammatory responses in a chronic restraint plus stress (CR+S) depression model and ex vivo hippocampal slices.