The Role of Neurotransmitters in MOGAD

Overview: MOGAD (Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease) is an inflammatory demyelinating disease of the central nervous system (CNS), driven by anti-MOG antibodies and immune cells targeting the myelin sheath, with perivenular myelin loss commonly observed and CD4⁺ T-cells, granulocytes, microglia, and activated complement deposits detected within lesions; growing evidence now suggests that neurotransmitter systems—often overlooked in this context—also play a crucial role by amplifying inflammation, disrupting neural signaling, and contributing to persistent symptoms such as neuropathic pain, fatigue, anxiety, and depression.

Possible Roles of Neurotransmitters in MOGAD Pathophysiology:

• Neuroinflammation and Immune Response:
CNS-resident cells such as microglia and astrocytes express receptors for various neurotransmitters. For instance, ATP and glutamate receptors regulate microglial migration and inflammatory signaling. Therefore, neuronal activity and neurotransmitter release directly influence microglial activation and cytokine production. Additionally, molecules like acetylcholine—released through the peripheral nervous system—also modulate inflammation. Both muscarinic and nicotinic acetylcholine receptors are present on immune and glial cells. In MS studies, decreased acetylcholine levels and increased acetylcholinesterase activity were associated with enhanced pro-inflammatory cytokine levels. Conversely, inhibitory neurotransmitters such as GABA (gamma-aminobutyric acid) exert immunosuppressive effects on immune and glial cells. The GABAergic system is closely linked to neuroimmune regulation and may serve as a therapeutic target to control brain inflammation. Thus, excitatory (e.g., glutamate) and inhibitory (e.g., GABA, acetylcholine) neurotransmitters play opposing roles during neuroinflammation.

• Myelin Damage and Glutamate Excitotoxicity:
Glutamate is the brain’s primary excitatory neurotransmitter, vital for synaptic transmission. However, excessive glutamate can overstimulate oligodendrocytes (myelin-producing cells), leading to excitotoxicity and cell death. These cells express AMPA and kainate-type glutamate receptors; their overactivation contributes to demyelination. In MS, glutamate is known to damage not only neurons but also oligodendrocytes, astrocytes, and even the blood-brain barrier. Lesions often show decreased glutamate transporter (EAAT) proteins and disrupted synaptic connectivity. That said, not all glutamate signaling is harmful: in some experimental models, glutamate released from neurons stimulated oligodendrocyte progenitor cells (OPCs), supporting remyelination. In summary, while glutamate excitotoxicity is a key pathological factor in MOGAD, glutamate signaling may also aid remyelination under controlled conditions.

• GABA and Other Neurotransmitters:
The GABAergic system is known for its inhibitory effects and plays a regulatory role in inflammation. Some studies suggest GABA stimulation may reduce immune activity and slow neurodegeneration. Although dopamine and serotonin also affect immune cell function, current data on their roles in MOGAD is limited. However, the cholinergic system is better understood: muscarinic receptor blockade in MS models has been shown to enhance oligodendrocyte maturation and promote remyelination, suggesting that acetylcholine signaling modulates both inflammation and repair.

• Dopamine:
Chronic inflammation alters dopamine activity in the basal ganglia. For example, primates treated with interferon-α showed significantly reduced levels of HVA, a dopamine metabolite. Previous studies, including Felger & Miller (2012), have shown that inflammatory cytokines can impair dopamine function in the basal ganglia—potentially contributing to symptoms such as fatigue, motor slowing, and anhedonia.. Elevated levels of TNF-α and IL-6 in MOGAD may contribute to dopamine depletion, thereby affecting motivation and mobility.

• Serotonin:
During acute inflammation, cytokines may transiently increase serotonin (5-HT) release, contributing to “sickness behaviors” like fever and appetite loss. However, in chronic inflammation, cytokines divert tryptophan metabolism toward the kynurenine pathway, decreasing central serotonin availability. In patients treated with interferon-α for hepatitis C, higher IL-6 levels correlated with reduced 5-HIAA (a serotonin metabolite) in cerebrospinal fluid and greater depression severity. Furthermore, TNF-α may increase serotonin reuptake transporter activity, lowering circulating 5-HT levels. In MOGAD, prolonged inflammation may accelerate serotonin turnover, depleting reserves and increasing the risk of mood disorders.

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The Role of β-Endorphins and the Opioid System in Inflamed Tissues (Outside MOGAD)

• Transport to Inflamed Sites:
Animal studies have shown β-endorphins and mu-opioid receptors are actively recruited to sites of inflammation, suggesting the body attempts to locally suppress pain and immune activity.

• Immune Effects:
In asthma models, β-endorphins inhibited the NF-κB pathway and reduced pro-inflammatory cytokines (TNF-α, IL-6). In bovine uterine cells, activation of δ-opioid receptors reduced inflammation.

• In Chronic Inflammatory Diseases:
In diseases like rheumatoid arthritis, increased levels of β-endorphins and enkephalins are believed to represent a compensatory, anti-inflammatory response to persistent immune activation. β-endorphins can increase anti-inflammatory cytokines (e.g., IL-10) and suppress pro-inflammatory mediators via mu-opioid receptors.

• In MOGAD:
Although direct data is lacking, the opioid system’s ability to modulate immune responses, particularly through NF-κB inhibition, suggests potential therapeutic relevance for MOGAD.

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Synaptic Transmission and Clinical Manifestations:
Demyelination slows or disrupts signal conduction along nerve fibers, leading to motor, sensory, or cognitive impairments. Studies of cortical lesions in MS have shown reduced synaptic protein levels accompanying myelin damage. In MOGAD, optic nerve and spinal cord lesions impair transmission and cause visual or motor dysfunction. Cortical involvement in some patients can even trigger seizures, indicating underlying synaptic dysfunction.

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Conclusions and Future Perspectives

1. Bidirectional Effects of Neurotransmitters:
Neurotransmitters may have both immunostimulatory and immunosuppressive effects depending on cell type, receptor subtype, and microenvironmental conditions.

2. Interaction with Inflammatory States:
Chronic inflammation (e.g., in tumor microenvironments) can enhance pro-inflammatory actions of dopamine, serotonin, substance P, and glutamate. However, in certain contexts, these molecules may also serve therapeutic roles to restore immune balance.

3. Receptor Diversity and Cell-Specific Responses:
The diversity of neurotransmitter receptors allows for nuanced, cell-specific immune modulation and opens the door for more targeted therapeutic approaches.

4. Evolutionary Perspective:
Neuro-immune communication is an evolutionarily conserved mechanism crucial for maintaining homeostasis. Even in model organisms like C. elegans, G-protein-coupled neurotransmitter receptors influence immune responses.

5. Psychosocial and Environmental Factors:
Emotional stress, circadian rhythms, and environmental changes modulate neuroimmune pathways. These findings highlight the direct impact of psychological and environmental factors on immune regulation.

6. Directions for Future Research:
• Opioid–immune interactions should be explored specifically in the context of MOGAD.
• Experimental models can help test the role of β‑endorphins in MOGAD-like disease processes.
• Patient studies may compare clinical levels of endorphins and cytokines to clarify neuroimmune interactions.

Neuroscientists are now exploring new therapeutic strategies aimed at reducing myelin loss and promoting repair by targeting neurotransmitter systems.

Single-cell analyses, genetic mapping, and systems biology approaches are expected to provide deeper insights into neuroimmune modulation.

These advances may enable the development of targeted neuroimmunotherapies, particularly for chronic inflammatory diseases.

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