Neuropharmacology of the Neuropsychiatric Symptoms of Dementia and Role of Pain: Essential Oil of Bergamot as a Novel Therapeutic Approach

Damiana Scuteri, Laura Rombolà, Luigi Antonio Morrone, Giacinto Bagetta, Shinobu Sakurada, Tsukasa Sakurada, Paolo Tonin, Maria Tiziana Corasaniti, Damiana Scuteri, Laura Rombolà, Luigi Antonio Morrone, Giacinto Bagetta, Shinobu Sakurada, Tsukasa Sakurada, Paolo Tonin, Maria Tiziana Corasaniti

Abstract

Aging of the population makes of dementia a challenge for health systems worldwide. The cognitive disturbance is a serious but not the only issue in dementia; behavioral and psychological syndromes known as neuropsychiatric symptoms of dementia remarkably reduce the quality of life. The cluster of symptoms includes anxiety, depression, wandering, delusions, hallucinations, misidentifications, agitation and aggression. The pathophysiology of these symptoms implicates all the neurotransmitter systems, with a pivotal role for the glutamatergic neurotransmission. Imbalanced glutamatergic and GABAergic neurotransmissions, over-activation of the extrasynaptic N-methyl-D-aspartate (NMDA) receptors and alterations of the latter have been linked to the development of neuropsychiatric symptoms experienced by almost the entire demented population. Drugs with efficacy and safety for prevention or long term treatment of these disorders are not available yet. Aromatherapy provides the best evidence for positive outcomes in the control of agitation, the most resistant symptom. Demented patients often cannot verbalize pain, resulting in unrelieved symptoms and contributing to agitation. Bergamot essential oil provides extensive preclinical evidence of analgesic properties. Incidentally, the essential oil of bergamot induces anxyolitic-like effects devoid of sedation, typical of benzodiazepines, with a noteworthy advantage for demented patients. These data, together with the reported safety profile, form the rational basis for bergamot as a neurotherapeutic to be trialed for the control of behavioral and psychological symptoms of dementia.

Keywords: aromatherapy; behavioral and psychological symptoms of dementia; bergamot essential oil; dementia; neuropsychiatric symptoms.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanism of BEO-induced increase of synaptic glutamate. BEO in low concentrations causes glutamate exocytosis, while in high concentrations it induces the release of glutamate through a carrier-mediated Ca2+-independent process [58].
Figure 2
Figure 2
Autophagy and analgesic activity of BEO. (A) LC3 expression in the hemi-cord contralateral (C) and ipsilateral (I) to the side of ligation, 7 days after Spinal Nerve Ligation (SNL), showing higher LC3-I expression in ipsilateral side of SNL mice and appearance of LC3-II, thus demonstrating a derangement of autophagy in this neuropathic pain model. The slight increase in LC3-I levels and the apparent formation of LC3-II well correlated with α2δ-1 upregulation (Sham: n = 5, SNL: n = 6; adapted with permission from reference [81]). (B) BEO-mediated concentration-dependent induction of autophagy in SH-SY5Y cells, demonstrated by immunoblot showing the conversion of LC3I to LC3II and reduced p62 levels. Histogram shows the densitometric analysis of p62 levels normalized on the values of GAPDH (used as loading control) expressed as percentage of vehicle from three independent experiments (mean ± SEM). * p < 0.05, ** p <0.01, *** p < 0.001 vs. 0.005% BEO (ANOVA followed by Tukey-Kramer multiple comparisons test; adapted with permission from reference [84]). (C) A daily dose of BEO (square; 1 mL/kg) subcutaneously administered for 7 days attenuated SNL-induced mechanical allodynia compared to vehicle (filled circles; *** p < 0.001). Open circles indicate mechanical sensitivity of sham operated mice. Data are expressed as mean ± SEM of 50% of pain threshold and normalized to the basal value of each animal (n = 5–10 per group). Differences are evaluated using one way analysis of variance (ANOVA), followed by Tukey multiple comparisons test. Adapted with permission from reference [76].

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Source: PubMed

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