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Study · Animal study (in vivo) · rat · 2026

10 results

Orforglipron, a Small-Molecule Glucagon-like Peptide-1 Receptor Agonist (GLP-1RA), Has Neuroprotective and Anti-Inflammatory Effects.

Li Y, Glotfelty EJ, Parekh P, Batsaikhan B, Luo W, Jackson SN, Harvey BK, Greig NH

Cells21 Jul 2026Cited by 1 (Europe PMC)

PMID42505410 (opens in a new tab)PMCIDPMC13406627 (opens in a new tab)DOI10.3390/cells15141301 (opens in a new tab)PepBankPUB-42505410
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Summary

GLP-1 receptor (GLP-1R) agonists, widely used for diabetes and obesity management, have shown preclinical and clinical promise as potential therapeutics for neurological conditions. Until 2026, all U.S. Food and Drug Administration (FDA)-approved GLP-1 drugs were peptide-based, with most requiring daily or weekly subcutaneous injections. Despite their large size and low brain penetrance, several peptide-based GLP-1 drugs are in clinical trials for neurologic indications. Recently, the FDA approved orforglipron as the first small-molecule, non-peptide, orally bioavailable human GLP-1 receptor agonist, and it may offer advantages over peptide-based counterparts. We hence evaluated whether it possesses similar neurotrophic, neuroprotective, and anti-inflammatory attributes. Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties. Orforglipron activated cAMP signaling and shielded neuronal cells from excitotoxic glutamate and oxidative stress, which are common in neurodegenerative diseases and injuries. Additionally, orforglipron effectively mitigated LPS- and glutamate-induced proinflammatory protein secretion (IL-6, IL-8, and MCP-1) from a human microglial cell line. Actions were replicated under insulin resistance-a potential cause of neurodegenerative conditions-in which orforglipron significantly upregulated phosphorylation of protein kinase B (Akt), providing an additional neuroprotective mechanism. Measured orforglipron brain uptake in rat was low (brain/plasma and CSF/plasma ratios: 0.0078), and in the ballpark of peptide-based GLP-1 drugs. Nevertheless, orforglipron may provide potential value in specific neurological conditions.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study10

10 results from studies that gave the peptide. No result from this study comes from people.

  1. 01AnimalAnimal study (in vivo)Pharmacokinetics

    In rats, orforglipron brain uptake was low, with a brain/plasma ratio of 0.0078.

    In plain wordsIn rats, orforglipron brain uptake was low.

    Peptide
    Orforglipron
    Outcome
    Not applicableBrain/plasma uptake ratio
    Study

    ratn: not reported in source

    Outcome group
    Pharmacokinetics · Pharmacology
    Studied dose
    Dose not stated

    Measurements

    Brain/plasma ratio
    0.0078 ratio
    rat

    Source sentences

    Summary
    Measured orforglipron brain uptake in rat was low (brain/plasma and CSF/plasma ratios: 0.0078), and in the ballpark of peptide-based GLP-1 drugs.
  2. 02AnimalAnimal study (in vivo)Pharmacokinetics

    In rats, orforglipron had a CSF/plasma ratio of 0.0078.

    In plain wordsIn rats, orforglipron levels in cerebrospinal fluid were low relative to plasma.

    Peptide
    Orforglipron
    Outcome
    Not applicableCSF/plasma uptake ratio
    Study

    ratn: not reported in source

    Outcome group
    Pharmacokinetics · Pharmacology
    Studied dose
    Dose not stated

    Measurements

    CSF/plasma ratio
    0.0078 ratio
    rat

    Source sentences

    Summary
    Measured orforglipron brain uptake in rat was low (brain/plasma and CSF/plasma ratios: 0.0078), and in the ballpark of peptide-based GLP-1 drugs.
  3. 03LabIn vitro (cells)Mechanism

    In human-derived cells, orforglipron activated cAMP signaling.

    In plain wordsIn cells, orforglipron activated cAMP signaling.

    Peptide
    Orforglipron
    Outcome
    IncreasecAMP signaling
    Study

    humann: not reported in source

    Human-derived neuronal and microglial cell lines
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Orforglipron activated cAMP signaling and shielded neuronal cells from excitotoxic glutamate and oxidative stress, which are common in neurodegenerative diseases and injuries.
    1 context sentence
    Summary · context
    Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties.
  4. 04LabIn vitro (cells)Efficacy outcome

    In human-derived neuronal cells, orforglipron protected against excitotoxic glutamate.

    In plain wordsIn cells, orforglipron protected neuronal cells against harmful glutamate exposure.

    Peptide
    Orforglipron
    Outcome
    IncreaseProtection from glutamate excitotoxicity
    Study

    humann: not reported in source

    Human-derived neuronal and microglial cell lines
    Outcome group
    Neuroprotection · Nervous system and cognition
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Orforglipron activated cAMP signaling and shielded neuronal cells from excitotoxic glutamate and oxidative stress, which are common in neurodegenerative diseases and injuries.
    1 context sentence
    Summary · context
    Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties.
  5. 05LabIn vitro (cells)Efficacy outcome

    In human-derived neuronal cells, orforglipron protected against oxidative stress.

    In plain wordsIn cells, orforglipron protected neuronal cells against oxidative stress.

    Peptide
    Orforglipron
    Outcome
    IncreaseProtection from oxidative stress
    Study

    humann: not reported in source

    Human-derived neuronal and microglial cell lines
    Outcome group
    Neuroprotection · Nervous system and cognition
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Orforglipron activated cAMP signaling and shielded neuronal cells from excitotoxic glutamate and oxidative stress, which are common in neurodegenerative diseases and injuries.
    1 context sentence
    Summary · context
    Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties.
  6. 06LabIn vitro (cells)Mechanism

    In human microglial cells, orforglipron reduced LPS- and glutamate-induced IL-6 secretion.

    In plain wordsIn cells, orforglipron reduced IL-6 secretion induced by LPS and glutamate.

    Peptide
    Orforglipron
    Outcome
    DecreaseIL-6 secretion
    Study

    humann: not reported in source

    Human-derived neuronal and microglial cell lines
    Outcome group
    Inflammation markers · Immune and inflammation
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Additionally, orforglipron effectively mitigated LPS- and glutamate-induced proinflammatory protein secretion (IL-6, IL-8, and MCP-1) from a human microglial cell line.
    1 context sentence
    Summary · context
    Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties.
  7. 07LabIn vitro (cells)Mechanism

    In human microglial cells, orforglipron reduced LPS- and glutamate-induced IL-8 secretion.

    In plain wordsIn cells, orforglipron reduced IL-8 secretion induced by LPS and glutamate.

    Peptide
    Orforglipron
    Outcome
    DecreaseIL-8 secretion
    Study

    humann: not reported in source

    Human-derived neuronal and microglial cell lines
    Outcome group
    Inflammation markers · Immune and inflammation
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Additionally, orforglipron effectively mitigated LPS- and glutamate-induced proinflammatory protein secretion (IL-6, IL-8, and MCP-1) from a human microglial cell line.
    1 context sentence
    Summary · context
    Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties.
  8. 08LabIn vitro (cells)Mechanism

    In human microglial cells, orforglipron reduced LPS- and glutamate-induced MCP-1 secretion.

    In plain wordsIn cells, orforglipron reduced MCP-1 secretion induced by LPS and glutamate.

    Peptide
    Orforglipron
    Outcome
    DecreaseMCP-1 secretion
    Study

    humann: not reported in source

    Human-derived neuronal and microglial cell lines
    Outcome group
    Inflammation markers · Immune and inflammation
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Additionally, orforglipron effectively mitigated LPS- and glutamate-induced proinflammatory protein secretion (IL-6, IL-8, and MCP-1) from a human microglial cell line.
    1 context sentence
    Summary · context
    Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties.
  9. 09LabIn vitro (cells)Mechanism

    In human-derived cells under insulin resistance, orforglipron significantly increased Akt phosphorylation.

    In plain wordsIn cells under insulin resistance, orforglipron increased Akt phosphorylation.

    Peptide
    Orforglipron
    Outcome
    IncreaseAkt phosphorylation under insulin resistance
    Study

    humann: not reported in source

    Human-derived neuronal and microglial cell lines
    Outcome group
    Receptor activity and mechanism · Nervous system and cognition
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Actions were replicated under insulin resistance-a potential cause of neurodegenerative conditions-in which orforglipron significantly upregulated phosphorylation of protein kinase B (Akt), providing an additional neuroprotective mechanism.
    1 context sentence
    Summary · context
    Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties.
  10. 10LabIn vitro (cells)Efficacy outcome

    In human-derived cell lines, orforglipron actions were replicated under insulin resistance.

    In plain wordsIn cells with insulin resistance, the researchers observed similar orforglipron actions.

    Peptide
    Orforglipron
    Outcome
    Direction not reportedReplication of cellular actions under insulin resistance
    Study

    humann: not reported in source

    Human-derived neuronal and microglial cell lines
    Outcome group
    Neuroprotection · Nervous system and cognition
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Actions were replicated under insulin resistance-a potential cause of neurodegenerative conditions-in which orforglipron significantly upregulated phosphorylation of protein kinase B (Akt), providing an additional neuroprotective mechanism.
    1 context sentence
    Summary · context
    Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 2Current

    14 Oct 2026, 05:02 UTC

    Study results updated

  2. Version 1

    14 Oct 2026, 01:46 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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