Mice from both the baicalin and fluoxetine groups show a decrease in depression-like behavior compared with controls. events which are implicated in psychiatric conditions [32,33,34] mimicking at some extent the mechanisms of action of conventional antidepressants and mood stabilizers in the absence of serious adverse effects [5,10,13,15,20,35,36] (Physique 1). Far from being the aim of the present manuscript is an attempt to deal with the neurobiology of depressive disorder, which is a complex, multifactorial disorder [33], here we limit to reviewing and discussing potential biochemical and molecular mechanisms through which the abovementioned compounds produce anxiolytic/antidepressant-like effects. In detail, bioactive compounds within and rescue alterations in monoamine and GABA neurotransmission, and they stimulate neurogenesis and the synthesis of neurotrophic factors while counteracting oxidative Lurasidone (SM13496) stress, mitochondrial dysfunction and inflammation (Physique 1) [5,6,7,8,9,10,11,12,13,14,15,20]. These herbs also modulate neuro-immune and neuro-endocrine functions by targeting hypothalamic-pituitary-adrenal (HPA) axis hyper-activation, which is implicated in mental disorders (Physique 1) [1,19,33]. Nonetheless, at a closer examination, each herb possesses specific effects by acting on different neurotransmitter systems and molecular pathways. After briefly summarizing the main herbal-related neuroprotective mechanisms which may be relevant for depressive disorders, we move to discuss evidence centred around the anxiolytic/antidepressant potential of each herb, as assessed specifically in experimental and clinical studies. Rabbit polyclonal to ACAD9 Open in a separate window Physique 1 A general view on the mechanisms of action of and against the main biological pathways that are altered in depressive disorder and depressive-like behavior (yellowish box). Hypotheses around the neurobiology of depressive disorder and stress are largely based on dysregulations of (i) neurotransmitter systems, including GABA and GABAA receptors [8], as well as monoamines (dopamine, norepinephrine and serotonin) [9]; (ii) hypothalamic-pituitary-adrenal (HPA) axis consisting of an abnormal release of corticotropin-releasing factor (CRH), adrenocorticotropin (ACTH) secretion from the Lurasidone (SM13496) anterior pituitary, abnormal secretion of glucocorticoids (cortisol in humans and corticosterone in rodents), activation of phosphorylated c-Jun kinase (pJNK), and aberrant unfavorable feedback HPA axis [9]. (iii) impaired neurotrophic mechanisms consisting of low expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), impaired neurogenesis and plasticity [9]; (iv) chronic oxidative stress and neuroinflammation [10]. Black T-shaped lines indicate inhibition. Red strong arrows indicate downregulation or hyperactivation. Red thin arrows indicate sequential molecular events. The still limited, although encouraging, results which emerge from both experimental and clinical studies underline the need for further investigations aimed at dissecting the fine molecular mechanisms of action as well as the safety and pharmacokinetic profiles of these herbal compounds. 2. and and are folk traditional medicinal herbs that gained increasing popularity for their health-promoting properties including antitumor, hepatoprotective, antimicrobial, anti-inflammatory, anti-hyperlipidemic, antidiabetic, cardio-protective, neurotrophic and neuroprotective effects [5,10,15,16,35,37,38,39,40,41,42,43,44,45,46,47]. In the brain, the beneficial effects of each herb are due to Lurasidone (SM13496) different bioactive compounds, Lurasidone (SM13496) some of which are able to cross the blood-brain-barrier (BBB). For these correspond to two major flavonoids, namely baicalin (glucuronide) and baicalein (aglycon), being purified from the plants dry roots (radix) [48]. possesses three main classes of bioactive compounds, namely polysaccharides, hericenones and erinacines, with the first two being extracted from the fruit bodies and the latter from the mycelia. Despite the widely reported beneficial effects of these bioactive ingredients in the brain, to date only erinacines have been documented to cross the BBB [49]. Eventually, the main bioactive compound of is usually salidroside glycone, which has been detected in the brain Lurasidone (SM13496) tissue as well [29,50,51]. Based on toxicological and clinical studies, and are generally considered to be safe and well tolerated [40,52,53,54,55,56,57,58,59,60,61,62,63]. In experimental studies, the estimated median lethal dose (LD50) of some compounds varies according to the extraction method and administration route [54]. In fact, as reported by pioneer toxicological studies, following subcutaneous injection in mice, the median lethal dose (LD50) of both ethanolic extract and isolated baicalin is usually 6 g/kg [54]. Instead, the LD50 of isolated baicalin following intraperitoneal injection is usually 3.081 g/kg [54]. More recently, 2.5 g/kg of ethanol extracts were shown to be.