Small molecules targeting PTPσ—Trk interactions promote sympathetic nerve regeneration

ACS Chem Neurosci, 2022 · DOI: 10.1021/acschemneuro.1c00854 · Published: March 2, 2022

Neurology Chemical Biology Regenerative Medicine & Stem Cells

Simple Explanation

Chondroitin Sulfate Proteoglycans (CSPGs) inhibit nerve regeneration after injuries like spinal cord injury or heart attack. This study focuses on developing small molecules to overcome this inhibition by targeting the interaction between PTPσ and Trk receptors. The researchers designed and synthesized small molecules (HJ-01, HJ-02) that disrupt the interaction between PTPσ and Trk receptors. These molecules enhance Trk signaling, which is important for nerve growth, and promote sympathetic nerve regeneration despite the presence of CSPGs. Contrary to their initial hypothesis, HJ-01 and HJ-02 do not directly inhibit the activity of PTPσ. Instead, they modulate the interaction between PTPσ and Trk receptors, preventing PTPσ from dephosphorylating and inhibiting Trk, thereby promoting nerve regeneration.

Study Duration

Not specified

Participants

Superior cervical ganglia from male and female neonatal rats

Evidence Level

Not specified

Key Findings

1
HJ-01 and HJ-02 restore sympathetic axon outgrowth over inhibitory CSPGs in a dose-dependent manner.
2
HJ-01 and HJ-02 do not inhibit PTPσ phosphatase activity at biologically relevant concentrations but disrupt the interaction between PTPσ and TrkA.
3
HJ-01 and HJ-02 reverse PTPσ-inhibition of Trk signaling, promoting ERK1/2 phosphorylation.

Research Summary

This study introduces novel small molecules, HJ-01 and HJ-02, designed to promote nerve regeneration through CSPG-containing scars by targeting PTPσ. These compounds restore nerve growth in vitro at nanomolar concentrations. The mechanism of action involves modulating PTPσ—Trk receptor signaling rather than directly inhibiting PTPσ phosphatase activity. HJ-01 and HJ-02 disrupt the interaction between PTPσ and TrkA, enhancing Trk signaling and promoting axon outgrowth. These small molecules hold promise as potential therapeutics for spinal cord injury, traumatic brain injury, and myocardial infarction, offering an advantage over peptide- and enzyme-based strategies due to their ease of production and administration.

Practical Implications

Therapeutic Potential

HJ-01 and HJ-02 could be developed as therapeutics for nerve regeneration in conditions such as spinal cord injury, traumatic brain injury, and myocardial infarction.

Drug Development

The findings suggest a new avenue for drug development targeting PTPσ-Trk interactions rather than direct PTPσ inhibition.

Overcoming CSPG Inhibition

These small molecules provide a means to overcome the inhibitory effects of CSPGs on nerve regeneration, offering a potential solution for promoting recovery after injury.

Study Limitations

1
Lack of direct binding data makes it impossible to rule out that HJ-01 and HJ-02 bind to an unidentified protein involved in PTPσ—Trk complex formation.
2
The concentration required to break Trk—PTP complexes was higher than the concentration that restored axon outgrowth.
3
Although our focus was on sympathetic neurons, CSPGs in the glial scar inhibit nerve regeneration after traumatic brain injury and spinal cord injury

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