Steroid and Xenobiotic Receptor Signalling in Apoptosis and Autophagy of the Nervous System

Abstract

Apoptosis and autophagy are involved in neural development and in the response of the nervous system to a variety of insults. Apoptosis is responsible for cell elimination, whereas autophagy can eliminate the cells or keep them alive, even in conditions lacking trophic factors. Therefore, both processes may function synergistically or antagonistically. Steroid and xenobiotic receptors are regulators of apoptosis and autophagy; however, their actions in various pathologies are complex. In general, the estrogen (ER), progesterone (PR), and mineralocorticoid (MR) receptors mediate anti-apoptotic signalling, whereas the androgen (AR) and glucocorticoid (GR) receptors participate in pro-apoptotic pathways. ER-mediated neuroprotection is attributed to estrogen and selective ER modulators in apoptosis- and autophagy-related neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, stroke, multiple sclerosis, and retinopathies. PR activation appeared particularly effective in treating traumatic brain and spinal cord injuries and ischemic stroke. Except for in the retina, activated GR is engaged in neuronal cell death, whereas MR signalling appeared to be associated with neuroprotection. In addition to steroid receptors, the aryl hydrocarbon receptor (AHR) mediates the induction and propagation of apoptosis, whereas the peroxisome proliferator-activated receptors (PPARs) inhibit this programmed cell death. Most of the retinoid X receptor-related xenobiotic receptors stimulate apoptotic processes that accompany neural pathologies. Among the possible therapeutic strategies based on targeting apoptosis via steroid and xenobiotic receptors, the most promising are the selective modulators of the ER, AR, AHR, PPARγ agonists, flavonoids, and miRNAs. The prospective therapies to overcome neuronal cell death by targeting autophagy via steroid and xenobiotic receptors are much less recognized.

Triclocarban Disrupts the Epigenetic Status of Neuronal Cells and Induces AHR/CAR-Mediated Apoptosis

“…This is because epidemiological data showed strong correlations between exposures to environmental pollutants and increased risks of disorders, including neuropsychiatric and neurodegenerative diseases. Apoptosis (“self-killing”) is involved in neural development and the response of the nervous system to a variety of insults by cell elimination which includes the pathogenesis of neural degeneration, such as stroke, Huntington’s, Parkinson’s, and Alzheimer’s diseases [ 11 ]. There is, however, no report showing that triclocarban induces apoptosis in mammalian neurons.…”

“…Nuclear receptors such as the AHR and CAR have been shown to be the mediators of xenobiotic-induced changes [ 11 , 13 ]. Until recently, AHR was almost exclusively considered to be responsible for dioxin and dioxin-like polychlorinated biphenyl (PCB) intoxications.…”

A Network Pharmacology Based Analysis of The Potential Mechanisms of Compound Danshen Dripping Pill for Treatment of Diabetic Retinopathy

“…51 Estrogen could be neuroprotective 52,53 or useless 54 or harmful 55 . Its neuroprotective effect may be related to anti-apoptosis and anti-autophagy effects, while androgen is more pro-apoptotic 56 . From our results, CDDP could have a potential in uence on both ESR and AR signaling.…”

Progesterone Effects in the Nervous System

“…Besides this, progesterone has been shown to promote neuroprotection after neonatal hypoxic brain injury, ischemic stroke, and TBI in animal models (Allitt et al, ; Dong et al, ; Tameh et al, ). Especially, the activation of progesterone receptor (PR) during treatment of the traumatic brain and ischemic stroke appeared to be particularly effective (Wnuk and Kajta, ). Stimulation with progesterone subsequent to a TBI enhances the protection against oxidative stress in juvenile murine neurons followed by decreased cerebral edema, apoptosis, and inflammatory reaction (Zhang et al, ).…”