Neuromodulating Action of Cimicifuga racemosa for Alleviation of Vasomotor Symptoms

 

Menopausal transition makes 50 to 85% of women experience symptoms affecting their well-being and quality of life. Licensed Cimicifuga racemosa (CR) medicinal products are efficacious against vasomotor symptoms (VMS), with isopropanolic extract (iCR) exhibiting best evidence [1, 2]. The mode of action is not fully known as the pathophysiology of VMS is still unclear. Circulating peripheral estrogen levels are not correlated with VMS [3]. The pace of estrogen depletion causes imbalances of serotonin- and noradrenalin levels (and others) in the thermoregulatory center, resulting in VMS [4 – 7]. The hypothalamic thermoregulatory center appears to be the most likely site of thermoregulatory dysfunction [8]. Hypothalamic KNDy neurons seem to participate in the generation of hot flushes [9]. Transformations in the postmenopausal brain include upregulation of KISS1 and TAC3 mRNA (encoding the KNDy-peptides kisspeptin and neurokinin) in distinct hypothalamic nuclei [10]. Also, calcitonin gene-related peptide seems to be involved in menopausal VMS [11]. References (e.g. MEDLINE, EMBASE, BIOSIS) was collected till 2019 and analyzed for CR interacting with brain receptors or modulating brain activity and brain metabolism.

iCR alleviates ovariectomy (OVX)-induced impaired thermoregulation [12]. iCR binds to serotonin, dopamine, GABA and µ-opioid brain receptors leading to receptor-mediated functional activity [13 – 16]. CR/iCR modulates the ratio of cerebral monoamines and metabolites [17] as well as serotonergic and dopaminergic brain activity (EEG) [18] and µ-opioid receptor availability [19]. In addition, iCR ameliorates OVX-induced changes of the serotonergic and noradrenergic brainstem-preoptic anterior hypothalamus pathways [20, 21]. OVX reduced the adaptability of hypothalamic neurons to respond to temperature changes and iCR compensated these changes by increasing neuronal activity [4, 22]. Moreover iCR/CR exerts anti-inflammatory, antioxidant and radical scavenger activity [23 – 28]. In distinct brain regions, iCR compensates OVX-induced upregulation of genes relevant for thermoregulation, mood, cognition and other menopause-associated dysfunctions [29].

These CR properties may be important as estrogen decline and fluctuations cause oxidative stress and neuroinflammation, resulting in „dysregulation” in the hypothalamic thermoregulatory area and possibly other central brain regions (e.g. hippocampus). We hypothesize that CR/iCR is able to initiate functional recovery of the hypothalamic thermo-regulatory area and thus, to mitigate VMS by a multifaceted set of mechanisms. These may include a direct action on serotonin, dopamine and µ-opioid receptors in connection with modulation of VMS-relevant gene expression and anti-inflammatory, antioxidant and radical scavenger activities.

The data show a non-estrogenic multi-target mode of action of CR alleviating menopausal symptoms including VMS. iCR binds to CNS receptors, modulates neuropeptide-based pathways, brain function and metabolism involved in thermoregulation and other climacteric symptoms. Further research is ongoing to elucidate the neuromodulating action of CR.

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