A Combined Chronic Low-Dose Soluble Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition Promotes Memory Reinstatement in Alzheimer’s Disease Mice Models

Abstract

Alzheimer’s disease (AD) is a progressive neurological disorder with multifactorial and heterogeneous causes. AD involves several etiopathogenic mechanisms such as aberrant protein accumulation, neurotransmitter deficits, synaptic dysfunction and neuroinflammation, which lead to cognitive decline. Unfortunately, the currently available anti-AD drugs only alleviate the symptoms temporarily and provide a limited therapeutic effect. Thus, new therapeutic strategies, including multitarget approaches, are urgently needed. It has been demonstrated that a co-treatment of acetylcholinesterase (AChE) inhibitor with other neuroprotective agents has beneficial effects on cognition. Here, we have assessed the neuroprotective effects of chronic dual treatment with a soluble epoxide hydrolase (sEH) inhibitor (TPPU) and an AChE inhibitor (6-chlorotacrine or rivastigmine) in in vivo studies. Interestingly, we have found beneficial effects after chronic low-dose co-treatment with TPPU and 6-chlorotacrine in the senescence-accelerated mouse prone 8 (SAMP8) mouse model as well as with TPPU and rivastigmine co-treatment in the 5XFAD mouse model, in comparison with the corresponding monotherapy treatments. In the SAMP8 model, no substantial improvements in synaptic plasticity markers were found, but the co-treatment of TPPU and 6-chlorotacrine led to a significantly reduced gene expression of neuroinflammatory markers, such as interleukin 6 (Il-6), triggering receptor expressed on myeloid cell 2 (Trem2) and glial fibrillary acidic protein (Gfap). In 5XFAD mice, chronic low-dose co-treatment of TPPU and rivastigmine led to enhanced protein levels of synaptic plasticity markers, such as the phospho-cAMP response element-binding protein (p-CREB) ratio, brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95), and also to a reduction in neuroinflammatory gene expression. Collectively, these results support the neuroprotectant role of chronic low-dose co-treatment strategy with sEH and AChE inhibitors in AD mouse models, opening new avenues for effective AD treatment.

Sex-Specific Response of the Brain Free Oxylipin Profile to Soluble Epoxide Hydrolase Inhibition

“…The sex of the mice studied was not specified; therefore, it is not possible to compare our sex differences findings to these results. Others have demonstrated that various sEHI compounds improve memory as measured by other cognitive function tests in the context of multiple disease models; however, these studies either only studied males, or combined males and females into one group [35][36][37][80][81][82][83][84][85]. Therefore, to our knowledge, our study is the first to describe sex differences in the effects of sEHI on murine behavior and memory.…”

“…Oxylipins are bioactive products of PUFA oxidation and have been demonstrated to play a role in neurological function, neuroinflammation, and neurodegenerative diseases, including dementias [8,11,12]. In addition, inhibition of sEH has been investigated as a potential therapeutic target for a wide range of neurological disorders, including dementias [13,21,22,26,30,31,[34][35][36][37]. Therefore, the impact of sEHI on the comprehensive profile of oxylipins is an important area of study to further understand how this treatment might be beneficial in neurodegenerative diseases such as dementia, a major global killer of men and women.…”

“…Research on sEH has implicated it as a treatment target for many disease types, including metabolic, inflammatory, and cardiovascular diseases [13,[16][17][18][19][20]. Further, sEH has been associated with, and the inhibition of its activity has been proposed as a treatment target for, diseases of the brain, including dementias [9,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. sEH inhibition has been demonstrated to positively impact modulation of neuronal activity, glial cell activity, cell survival, neuroinflammation, blood flow, and blood-brain barrier permeability; further, it has been suggested that many of these benefits are due to the subsequent increase in epoxy-fatty acid levels, in particular, the levels of EpETrEs [41][42][43][44][45][46][47].…”