Lysophospholipid receptors in neurodegeneration and neuroprotection

Explor Neuroprotective Ther., 2024 · DOI: 10.37349/ent.2024.00088 · Published: January 1, 2024

Simple Explanation

The central nervous system (CNS) cannot regenerate, making damage often permanent and leading to neurodegeneration. Neuroprotection strategies are thus critical for medical advances. Lysophospholipids like S1P and LPA bind to GPCRs, playing roles in physiology and disease. Fingolimod, an S1P receptor agonist, shows neuroprotective effects in multiple neuropathologies. LPA receptors, particularly LPA1, are upregulated in neuropathologies. Antagonists or mutations of LPA receptors are neuroprotective in conditions like cortical development and brain injury.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
Fingolimod, an S1P receptor agonist, is clinically effective in multiple sclerosis and shows neuroprotective effects in various neuropathologies, including stroke and Alzheimer’s disease.
2
Antagonists or mutations of LPA receptors, especially LPA1, are neuroprotective in several conditions, such as cortical development, traumatic brain injury, and stroke.
3
S1P receptor activation can increase brain-derived neurotrophic factor (BDNF) expression, promoting neuron survival and improving motor function in conditions like Rett syndrome and Huntington’s disease.

Research Summary

This review describes the roles of S1P and LPA receptors in neurodegeneration and potential neuroprotection. Fingolimod, an S1P receptor agonist, is clinically used for multiple sclerosis and shows neuroprotective properties in other neurological diseases. LPA receptors, particularly LPA1, are upregulated in neuropathologies, and their antagonists or mutations demonstrate neuroprotective effects in conditions like traumatic brain injury and stroke. Interactions between GPCRs and other receptors, such as PRGs with LPA receptors, suggest a complex regulatory network influencing receptor signaling and neuroprotection.

Practical Implications

Therapeutic Potential of S1P Receptors

Fingolimod's success in MS highlights S1P receptors as therapeutic targets for neurodegenerative diseases, warranting further development of specific S1P receptor agonists and antagonists.

Targeting LPA Receptors for Neuroprotection

The neuroprotective effects of LPA receptor antagonism suggest potential therapies for conditions like traumatic brain injury and stroke, emphasizing the need for LPA receptor-specific pharmacological tools.

BDNF-mediated Neuroprotection

The involvement of BDNF in S1P receptor-mediated neuroprotection indicates that strategies to enhance BDNF expression could improve outcomes in neurodegenerative diseases like Alzheimer's and Huntington's disease.

Study Limitations

1
Limited well-characterized pharmacological compounds for LPA receptors.
2
Whether activation or inhibition of S1P receptors is neuroprotective varies.
3
Need for more investigation of interactions between GPCRs and other receptors.

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