Rivastigmine Improves Appetite by Increasing the Plasma Acyl/Des-Acyl Ghrelin Ratio and Cortisol in Alzheimer Disease

Abstract

Background: Weight loss accelerates cognitive decline and increases mortality in patients with dementia. While acetylcholinesterase (AChE) inhibitors are known to cause appetite loss, we sometimes encounter patients in whom switching from donepezil (AChE inhibitor) to rivastigmine (AChE and butyrylcholinesterase [BuChE] inhibitor) improves appetite. Since BuChE inactivates ghrelin, a potent orexigenic hormone, we speculated that rivastigmine improves appetite by inhibiting BuChE-mediated ghrelin inactivation. Methods: The subjects were patients with mild to moderate Alzheimer disease treated with either rivastigmine patch (n = 11) or donepezil (n = 11) for 6 months. Before and after treatment, we evaluated appetite (0, decreased; 1, slightly decreased; 2, normal; 3, slightly increased; 4, increased), cognitive function, and blood biochemical variables, including various hormones. Results: Rivastigmine treatment significantly improved appetite (from 1.6 ± 0.5 to 2.6 ± 0.7), whereas donepezil treatment did not (from 2.0 ± 0.0 to 1.8 ± 0.4). Simultaneously, rivastigmine, but not donepezil, significantly decreased the serum cholinesterase activity (from 304.3 ± 60.5 to 246.8 ± 78.5 IU/L) and increased the cortisol level (from 11.86 ± 3.12 to 14.61 ± 3.29 μg/dL) and the acyl/des-acyl ghrelin ratio (from 4.03 ± 2.96 to 5.28 ± 2.72). The levels of leptin, insulin, total ghrel­in, and cognitive function were not significantly affected by either treatment. Conclusions: Our results suggest that compared with donepezil, rivastigmine has the advantage of improving appetite by increasing the acyl/des-acyl ghrelin ratio and cortisol level, thereby preventing weight loss.

The Potential Roles of Ghrelin in Metabolic Syndrome and Secondary Symptoms of Alzheimer’s Disease

“…Shadowed background color indicates the beneficial effects of ghrelin on metabolic syndrome and secondary symptoms of Alzheimer's disease. (Furiya et al, 2018) implying AD-related cachexia could potentially be alleviated by promoting appetite through ghrelin administration. Thus, the orexigenic effect of ghrelin may prevent the loss of body weight and lean mass in AD patients.…”

“…In addition, ghrelin administration stimulated cerebral responses to food in the amygdala, anterior insula, orbitofrontal cortex, and striatum of healthy subjects ( Malik et al, 2008 ). Interestingly, rivastigmine administration increased appetite by increasing acyl-ghrelin/des-acyl-ghrelin ratio in AD patients ( Furiya et al, 2018 ) implying AD-related cachexia could potentially be alleviated by promoting appetite through ghrelin administration. Thus, the orexigenic effect of ghrelin may prevent the loss of body weight and lean mass in AD patients.…”

Appetite, Metabolism and Hormonal Regulation in Normal Ageing and Dementia

“…Galantamine-induced adiponectin augmentation and HOMA-IR amelioration have been reported so far in one study in young adults with metabolic syndrome within 4 weeks [ 165 ]. On the contrary, rivastigmine, capable also of inhibiting the ghrelin degrading enzyme butyrylcholine esterase, has a direct effect on appetite and the prevention of weight loss, without affecting leptin levels [ 166 , 167 ].…”

“…The perspective pharmacological interventions in the sub-group of MCI cases whose deterioration is anticipated [ 2 , 181 ] could be beneficial in alleviating appetite/eating disturbances and providing tailored solutions, due to the divergent actions of ACHEIs [ 164 , 165 , 166 , 167 ]. The NMDA antagonist memantine has been also reported capable to mitigate overall NPI prevalence in combined schemes with donepezil, and especially up to 4.8 points in replacement schemes [ 182 ], with significant improvement of the appetite/eating cluster, possibly due to the normalization of binge-eating [ 183 ].…”

The Use of Anti-Diabetic Drugs in Alzheimer’s Disease, New Therapeutic Options and Future Perspective

“…Rivastigmine. This is also a cholinesterase inhibitor used to enhance cholinergic stimulation [24]. Gestational diabetes develops in pregnant women when cortisol, estrogen and lactogen produced by the placenta can block insulin resulting in insulin resistance.…”