Some Candidate Drugs for Pharmacotherapy of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD; progressive neurodegenerative disorder) is associated with cognitive and functional impairment with accompanying neuropsychiatric symptoms. The available pharmacological treatment is of a symptomatic nature and, as such, it does not modify the cause of AD. The currently used drugs to enhance cognition include an N-methyl-d-aspartate receptor antagonist (memantine) and cholinesterase inhibitors. The PUBMED, Medical Subject Heading and Clinical Trials databases were used for searching relevant data. Novel treatments are focused on already approved drugs for other conditions and also searching for innovative drugs encompassing investigational compounds. Among the approved drugs, we investigated, are intranasal insulin (and other antidiabetic drugs: liraglitude, pioglitazone and metformin), bexarotene (an anti-cancer drug and a retinoid X receptor agonist) or antidepressant drugs (citalopram, escitalopram, sertraline, mirtazapine). The latter, especially when combined with antipsychotics (for instance quetiapine or risperidone), were shown to reduce neuropsychiatric symptoms in AD patients. The former enhanced cognition. Procognitive effects may be also expected with dietary antioxidative and anti-inflammatory supplements—curcumin, myricetin, and resveratrol. Considering a close relationship between brain ischemia and AD, they may also reduce post-brain ischemia neurodegeneration. An investigational compound, CN-105 (a lipoprotein E agonist), has a very good profile in AD preclinical studies, and its clinical trial for postoperative dementia is starting soon.

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

“…In this regard, in a combinatory therapy with 3 or 4 drugs (anticholinergics, memantine, aducanumab, sodium oligomannate (GV-971), antiinflammatories) it may be interesting to add a drug such as metformin, which may be key in improving hypometabolism and increasing glucose uptake in the brain. For this reason, metformin (or other antidiabetic drugs) can provide added value by increasing glucose transport to neurons and increasing ATP levels [65,[149][150][151][152][153]. Thus, based on literature, metformin can be used to inhibit dementia progression and can be a novel therapeutic medication for strengthening LOAD-related cognitive dysfunction [65].…”

“…It has been reported that metformin decreases the levels of IL-1β and IL-6 in APP/PS1 mice [76]. In addition, different studies have highlighted the anti-inflammatory and antioxidant function of metformin, with several pathways playing a key role in the activation of AMPK [147][148][149][150][151][152]. In certain cases, metformin suppresses inflammation and decreases or removes inflammatory factors largely by dependent pathways and often independently of AMPK at the cellular level and elsewhere at the systemic level [148,149].…”

“…On another front, it has been reported that metformin can decrease ROS production through direct inhibition of the chain of the electron transfer complex of complex I (NADH ubiquitin oxidoreductase (NADH) [ 151 , 152 , 153 ]. Other described mechanisms involved in the reduction of ROS may be due to the activation of antioxidant enzymes such as catalase, which is the main decomposer of H 2 O 2 , inducing the endogenous antioxidant system that includes glutathione reductase (GSH), superoxide dismutase (SOD), and catalase (CAT [ 151 , 152 ]. It has also been described that metformin can stabilize the nuclear factor related to erythroid 2 (Nrf2), a sensor of oxidative stress, and induce its gene expression, through AMPK.…”

The Rhesus Macaque as a Translational Model for Neurodegeneration and Alzheimer’s Disease

“…There has been very limited efficacy in preventing the onset of some new memory-related symptoms with memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, cholinesterase inhibiters such as donepezil, and a recently approved combination of the two classes (Miziak et al, 2021). However, there are no current interventions which treat the etiology of or even prevent the progression of AD, in spite of many studies and clinical trials (i.e., Farlow et al, 2012;Ostrowitzki et al, 2017;Cummings et al, 2018;Egan et al, 2019;Haass and Levin, 2019).…”

Antidepressants in Alzheimer’s Disease: A Focus on the Role of Mirtazapine

“…This leads to the possibility of mirtazapine to be administered in a combination therapy for AD patients, eventually leading to better outcomes by targeting different signaling pathways [ 114 , 121 ]. Additionally, the combination of antipsychotics (such as risperidone and quetiapine) and mirtazapine may be also observed in AD therapeutic regimens [ 122 , 123 ].…”