MA-[D-Leu-4]-OB3, a small molecule synthetic peptide leptin mimetic, improves episodic memory, and reduces serum levels of tumor necrosis factor-alpha and neurodegeneration in mouse models of Type 1 and Type 2 Diabetes Mellitus

Hirschstein, Zall; Vanga, Gautam; Wang, Guirong; Novakovic, Zachary M.; Grasso, Patricia

doi:10.1016/j.bbagen.2020.129697

Cited by 7 publications

(3 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MA-[D-Leu-4]-OB3, the myristic acid (MA) conjugate of [D-Leu-4]-OB3 (Ser-Cys-Ser-dLeu-Pro-Gln-Thr), 19 was prepared commercially at >97% purity as a C-terminal amide by Atlantic Peptides (Lewisburg, PA, USA). MA-[D-Leu-4]-OB3 was dissolved in vehicle (.3% dodecyl maltoside, DDM, trade name Intravail®, Aegis Therapeutics, San Diego, CA, USA, reconstituted in sterile deionized water), and delivered by oral gavage (100 μL) once daily between 16:00 and 17:00 h. This time-frame was chosen based on the active feeding time of the mice (after lights out at 19:00 h), and the pharmacokinetics of MA-[D-Leu-4]-OB3: the maximum concentration (C max ) following oral delivery is reached at 4 h (T max ), and the half-life (T 1/2 ) is 29 h. 16…”

Section: Methodsmentioning

confidence: 99%

“…12 This peptide has been modified over the years to improve its efficacy, pharmacokinetics, and method of delivery in a number of mouse models of human disease. [13][14][15][16][17][18][19][20] Most worthy of special note is the proven ability of these leptin mimetics to cross the BBB and to localize in the hypothalamus in all mouse models tested, 17 thus overcoming the central resistance associated with common obesity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice

2023

Self Cite

View full text Add to dashboard Cite

Although the regulatory influence of leptin on energy balance, glycemic control, immunity, reproduction, and cognition is well established, its clinical application to common obesity and its co-morbidities has been limited by impaired transport across the blood-brain barrier, and tendencies to induce adverse side effects. To circumvent these drawbacks, MA-[D-Leu-4]-OB3, a leptin-related synthetic peptide that mimics the metabolic and neurotrophic effects of leptin in mouse models of genetic and non-genetic obesity, diabetes, and cognitive dysfunction, has been developed. This report presents the results of our initial efforts to assess the safety of orally delivered MA-[D-Leu-4]-OB3. Two pre-clinical studies were done in male and female C57BL/6 mice: a short-term study with a high dose of MA-[D-Leu-4]-OB3 (50 mg/kg/100 μL/day) and a dose-response study with 3 increasing concentrations of MA-[D-Leu-4]-OB3 (16.6, 50, and 150 mg/kg/100 μL/day). Body weight, food and water intake, glucose tolerance, and episodic memory were evaluated. Once-daily cage-side clinical observations were conducted to detect any physical or behavioral indicators of toxicity. Our results indicate that all metabolic and neurologic endpoints tested were either unaffected or improved by MA-[D-Leu-4]-OB3, and no clinical indicators of toxicity were evident. Together with our previously reported efficacy data, these results provide additional evidence supporting further development of this novel synthetic peptide leptin mimetic as a first-in-class peptide drug candidate for the treatment of a number of metabolic and/or cognitive dysfunctions in humans.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice

2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…A recently-published follow-up study indicated that the mechanism of action by which MA-[D-Leu-4]-OB3 improves cognitive function in these mouse models appears to be related to its ability to enhance insulin sensitivity peripherally and in the brain, and to reduce TNF-α-induced neurodegeneration (Hirschstein et al, 2020). Most recently, the prophylactic capacity of MA-[D-Leu-4]-OB3 to prevent or slow the progression of obesity, insulin resistance, and cognitive impairment in a mouse model of T2DM has been reported (Chua et al, 2021).…”

Section: Assessing the Effects Of Leptin Mimetics On Cognitive Functionmentioning

confidence: 99%

Harnessing the Power of Leptin: The Biochemical Link Connecting Obesity, Diabetes, and Cognitive Decline

Grasso

2022

Front. Aging Neurosci.

Self Cite

View full text Add to dashboard Cite

In this review, the current understanding of leptin’s role in energy balance, glycemic regulation, and cognitive function is examined, and its involvement in maintaining the homeostatic “harmony” of these physiologies is explored. The effects of exercise on circulating leptin levels are summarized, and the results of clinical application of leptin to metabolic disease and neurologic dysfunction are reviewed. Finally, pre-clinical evidence is presented which suggests that synthetic peptide leptin mimetics may be useful in resolving not only the leptin resistance associated with common obesity and other elements of metabolic syndrome, but also the peripheral insulin resistance characterizing type 2 diabetes mellitus, and the central insulin resistance associated with certain neurologic deficits in humans.

show abstract

Prophylactic Application of MA-[d-Leu-4]-OB3, a Small Molecule Synthetic Peptide Leptin Mimetic, Prevents or Slows the Progression of Obesity, Insulin Resistance, and Cognitive Impairment in a Mouse Model of Type 2 Diabetes Mellitus

Chua

Novakovic

Grasso

2021

Int J Pept Res Ther

View full text Add to dashboard Cite

MA-[D-Leu-4]-OB3, a small molecule synthetic peptide leptin mimetic, improves episodic memory, and reduces serum levels of tumor necrosis factor-alpha and neurodegeneration in mouse models of Type 1 and Type 2 Diabetes Mellitus

Cited by 7 publications

References 30 publications

Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice

Assessing the Safety of MA-[D-Leu-4]-OB3, a Synthetic Peptide Leptin Mimetic: Two Pre-Clinical Toxicity Studies in Male and Female C57BL/6 Mice

Harnessing the Power of Leptin: The Biochemical Link Connecting Obesity, Diabetes, and Cognitive Decline

Prophylactic Application of MA-[d-Leu-4]-OB3, a Small Molecule Synthetic Peptide Leptin Mimetic, Prevents or Slows the Progression of Obesity, Insulin Resistance, and Cognitive Impairment in a Mouse Model of Type 2 Diabetes Mellitus

Contact Info

Product

Resources

About