Aging is a complex biological process that increases the risk of age-related cognitive degenerative diseases such as dementia, including Alzheimer’s disease (AD), Lewy Body Dementia (LBD), and mild cognitive impairment (MCI). Even non-pathological aging of the brain can involve chronic oxidative and inflammatory stress, which disrupts the communication and balance between the brain and the immune system. There has been an increasingly strong connection found between chronic neuroinflammation and impaired memory, especially in AD. While microglia and astrocytes, the resident immune cells of the central nervous system (CNS), exerting beneficial effects during the acute inflammatory phase, during chronic neuroinflammation they can become more detrimental. Central cholinergic circuits are involved in maintaining normal cognitive function and regulating signaling within the entire cerebral cortex. While neuronal-glial cholinergic signaling is anti-inflammatory and anti-oxidative, central cholinergic neuronal degeneration is implicated in impaired learning, memory sleep regulation, and attention. Although there is evidence of cholinergic involvement in memory, fewer studies have linked the cholinergic anti-inflammatory and anti-oxidant pathways to memory processes during development, normal aging, and disease states. This review will summarize the current knowledge of cholinergic effects on microglia and astroglia, and their role in both anti-inflammatory and anti-oxidant mechanisms, concerning normal aging and chronic neuroinflammation. We provided details on how stimulation of α7 nicotinic acetylcholine (α7nACh) receptors can be neuroprotective by increasing amyloid-β phagocytosis, decreasing inflammation and reducing oxidative stress by promoting the nuclear factor erythroid 2-related factor 2 (Nrf2) pathways and decreasing the release of pro-inflammatory cytokines. There is also evidence for astroglial α7nACh receptor stimulation mediating anti-inflammatory and antioxidant effects by inhibiting the nuclear factor-κB (NF-κB) pathway and activating the Nrf2 pathway respectively. We conclude that targeting cholinergic glial interactions between neurons and glial cells via α7nACh receptors could regulate neuroinflammation and oxidative stress, relevant to the treatment of several neurodegenerative diseases.

Summary:  Purpose: The possible role of gap junctions in the manifestation and control of the duration of seizures was tested on the 4‐aminopyridine–induced epilepsy model in rats in vivo, by using electrophysiologic, pharmacologic, and molecular biologic techniques. Methods: In electrophysiologic experiments, the functional states of the gap junctions were manipulated with a specific blocker (carbenoxolone) or opener (trimethylamine) at the already active focus of adult, anesthetized rats, 60 min after the induction of the first seizure, which was repeated spontaneously thereafter. Semiquantitative reverse transcriptase–polymerase chain reaction (RT‐PCR) amplification was used to measure the levels of connexin (Cx) 32, 43, and 36 messenger RNAs (mRNAs) prepared from the areas of the already active primary and mirror foci. Results: After repeated seizures, the expression levels of Cx32, Cx43, and Cx36 mRNAs at the epileptic foci were increased significantly. Blockade of the gap junctions with carbenoxolone shortened the duration of seizures and decreased the amplitude of the seizure discharges, whereas their opening with trimethylamine lengthened the duration and increased the amplitude. Secondary epileptogenesis was facilitated when the gap junctions were opened. Conclusions: Our findings support the idea that, in epileptic foci, the gap junctions are involved in the expression of rhythmic ictal discharges and in the control of the duration and propagation of the individual seizures in vivo.

Chronic neuroinflammation is now considered one of the major factors in the pathogenesis of Alzheimer’s disease (AD). However, the most widely used transgenic AD models (overexpressing mutated forms of amyloid precursor protein, presenilin, and/or tau) do not demonstrate the degree of inflammation, neurodegeneration (particularly of the cholinergic system), and cognitive decline that is comparable with the human disease. Hence a more suitable animal model is needed to more closely mimic the resulting cognitive decline and memory loss in humans in order to investigate the effects of neuroinflammation on neurodegeneration. One of these models is the glial fibrillary acidic protein-interleukin 6 (GFAP-IL6) mouse, in which chronic neuroinflammation triggered constitutive expression of the cytokine interleukin-6 (IL-6) in astrocytes. These transgenic mice show substantial and progressive neurodegeneration as well as a decline in motor skills and cognitive function, starting from 6 months of age. This animal model could serve as an excellent tool for drug discovery and validationin vivo. In this review, we have also selected three potential anti-inflammatory drugs, curcumin, apigenin, and tenilsetam, as candidate drugs, which could be tested in this model.