Progesterone: Exploring its Neuroprotective Potential in the Enteric Nervous System


Progesterone, a well-known sexual hormone, is a steroid hormone that plays a crucial role in female reproduction. However, recent studies have shed light on its diverse effects beyond reproductive functions.

It has been implicated in cancer biology and recognized as a neurosteroid in both the central nervous system (CNS) and peripheral nervous system (PNS). Progesterone exhibits various neuroprotective and neuroplastic effects in the CNS and PNS, and a groundbreaking study has recently revealed its neuroprotective potential in the enteric nervous system (ENS) as well [1-7].

The ENS, often referred to as the “second brain,” is an intricate network of approximately 100 million neurons residing in the gut wall. It is comprised of two main plexus known as the submucosal and myenteric plexus. This autonomous network exhibits a level of complexity comparable to the CNS, with a wide array of neurotransmitters, functionally distinct enteric neurons, and glial cells [8,9].

The bidirectional communication network between the ENS and CNS, known as the gut-brain axis, has emerged as a crucial factor in the pathogenesis of neurodegenerative disorders like Parkinson’s disease (PD) [10,11].

Studies have indicated that misfolded alpha-synuclein aggregates, called Lewy bodies, first appear in the ENS and subsequently spread to the CNS via the vagal nerve, potentially contributing to the development of PD [12,13,14]. PD is characterized by the loss of dopaminergic neurons in the brainstem area of the CNS, which leads to the typical hypokinetic symptoms of the disease.

Interestingly, a similar loss of dopaminergic neurons has also been observed in the human ENS [15]. Currently, four different toxin-induced models are used to simulate PD, including 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), paraquat, and rotenone.

These models generate oxidative stress, resulting in the death of dopaminergic neuronal populations and the manifestation of PD symptoms at the cellular and behavioral levels. Rotenone, in particular, has been found to induce alpha-synuclein aggregates [16,17,18].

Despite recent advancements in our understanding of PD pathogenesis, there has been limited research on the neuroprotective potential of progesterone in the ENS. It is essential to investigate the extent to which progesterone can exert a neuroprotective effect in the ENS, particularly in the context of neurodegenerative diseases.

Therefore, this study aims to explore the expression of progesterone receptors in the ENS at various developmental stages and evaluate the neuroprotective effects of progesterone on rotenone-treated neurons in dissociated ENS cultures. Furthermore, potential mechanisms of action will be discussed.

To begin the investigation, the expression of progesterone receptors in the ENS will be examined at different time points during development. This analysis will help elucidate the presence and potential roles of progesterone receptors in the enteric neurons and glial cells of the ENS.

Subsequently, rotenone-induced neurotoxicity will be simulated in dissociated ENS cultures to evaluate the neuroprotective effects of progesterone. The cultures will be treated with rotenone, and the subsequent addition of progesterone will determine its ability to mitigate neuronal cell death and preserve the integrity of the ENS. Various cellular and molecular assays can be employed to assess cell viability, neuronal morphology, and the expression of neuroprotective markers.

Furthermore, the potential mechanisms underlying progesterone’s neuroprotective effects in the ENS need to be investigated. Progesterone’s actions may involve multiple pathways, including anti-inflammatory effects, modulation of oxidative stress, and regulation of apoptotic pathways.

These mechanisms can be explored through gene expression analysis, protein profiling, and signaling pathway investigations. Additionally, the interaction between progesterone and other components of the gut-brain axis, such as the gut microbiota, immune cells, and neurotransmitters, should be considered to comprehensively understand the neuroprotective potential of progesterone in the ENS.

In conclusion, progesterone, known primarily for its role in female reproduction, exhibits remarkable neuroprotective potential in the ENS.

What are the links between Progesterone and Alzheimer’s?

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra region of the brain. This loss of neurons leads to the typical motor symptoms of PD, including tremors, rigidity, and bradykinesia. While current treatments for PD focus on managing symptoms, there is a growing interest in identifying neuroprotective therapies that can slow or halt the progression of the disease.

Progesterone, a steroid hormone primarily known for its role in female reproduction, has been recognized for its neuroprotective properties in various neurological conditions. Recent research has shed light on the potential of progesterone as a treatment option for PD. Studies have demonstrated that progesterone exhibits neuroprotective effects in both the central nervous system (CNS) and peripheral nervous system (PNS), and its efficacy in protecting dopaminergic neurons holds promise for PD treatment [1-6].

One of the key mechanisms underlying the neuroprotective effects of progesterone is its ability to modulate inflammation. Inflammation plays a significant role in the progression of neurodegenerative diseases, including PD. Progesterone has been shown to suppress pro-inflammatory cytokines and promote anti-inflammatory factors, thereby reducing neuroinflammation and protecting neurons from damage [7,8]. By attenuating neuroinflammation, progesterone may help preserve dopaminergic neurons and slow down the progression of PD.

Another crucial aspect of progesterone’s neuroprotective action is its antioxidant properties. Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and antioxidant defenses, is a hallmark of PD. Studies have demonstrated that progesterone acts as an antioxidant, scavenging free radicals and reducing oxidative stress-induced damage to neurons [9,10]. By mitigating oxidative stress, progesterone may protect dopaminergic neurons from degeneration in PD.

Furthermore, progesterone has been shown to promote neuroplasticity and enhance neuronal survival. It stimulates the production of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which play a crucial role in supporting the growth, survival, and maintenance of neurons [11,12]. The preservation of dopaminergic neurons through the promotion of neuroplasticity may have significant implications for PD treatment.

In addition to its direct neuroprotective effects, progesterone also exerts modulatory actions on the gut-brain axis, which has been implicated in PD pathogenesis. The enteric nervous system (ENS), often referred to as the “second brain,” is a complex network of neurons located in the gastrointestinal tract. Emerging evidence suggests that dysfunction of the ENS and impaired gut-brain communication contribute to PD development [13,14]. Interestingly, progesterone has been found to have a neuroprotective effect in the ENS as well [7]. By targeting both the CNS and ENS, progesterone may provide comprehensive neuroprotection and potentially mitigate the progression of PD through the gut-brain axis.

Although the neuroprotective potential of progesterone in PD is promising, further research is needed to fully understand its mechanisms of action and optimize its therapeutic use. Clinical trials are necessary to evaluate the efficacy, safety, and optimal dosage of progesterone in PD patients. Additionally, studies focusing on the timing of progesterone administration and its combination with existing PD treatments could provide valuable insights into its synergistic effects and potential for combination therapy.

Considering the involvement of the ENS in neurodegenerative diseases like PD and the growing significance of the gut-brain axis, further research on progesterone’s neuroprotective effects in the ENS is warranted. This investigation, which explores the expression of progesterone receptors in the ENS at different developmental stages and evaluates progesterone’s neuroprotective effects on rotenone-treated neurons, will contribute to our understanding of the potential therapeutic applications of progesterone in neurodegenerative disorders. Ultimately, this research may pave the way for novel treatment strategies targeting the ENS and the gut-brain axis, opening up new avenues for combating neurodegenerative diseases like PD.


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