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Innovative Medicines & Omics Peganum harmala and GLP-1: A natural approach

in neuronal glucose metabolism and insulin sensitivity. oxidative stress, which is central to the pathophysiology of
5,7
Both compounds influence the PI3K/Akt pathway, a neurodegenerative diseases. These mechanisms position
critical mediator of cellular survival, growth, and glucose P. harmala as a potential therapeutic agent for disorders
uptake. By enhancing the phosphorylation of Akt at characterized by impaired glucose metabolism and
serine 473 (pS473-Akt), harmine and harmaline promote elevated oxidative stress, such as AD and other forms of
the downstream activation of GLUT4, a transmembrane cognitive decline. 5,7,12,14,15
protein essential for neuronal glucose uptake. 8 3. The systemic importance of

This process begins with the binding of insulin or GLP-1 GLP-1: Physiological roles and mechanisms
to their respective receptors, leading to the recruitment
and activation of PI3K. PI3K catalyzes the conversion GLP-1 is a multifunctional hormone that plays a central
of phosphatidylinositol 4,5-bisphosphate (PIP2) to role in maintaining glucose homeostasis and regulating
phosphatidylinositol 3,4,5-trisphosphate (PIP3), which metabolic processes at the systemic level. Synthesized and
acts as a docking site for Akt. Harmine and harmaline secreted primarily by enteroendocrine L-cells of the small
potentiate this signaling cascade, ensuring sustained intestine in response to nutrient ingestion, GLP-1 exerts its
activation of Akt. The activated Akt phosphorylates effects through the GLP-1R, which is widely expressed in
9
downstream targets, including AS160, which facilitates the pancreatic islets, the brain, and peripheral tissues. 16
translocation of GLUT4 vesicles to the neuronal plasma GLP-1 is a critical regulator of blood glucose levels
membrane, enhancing glucose uptake into neurons. 10 through its glucose-dependent actions on pancreatic
Harmine and harmaline exert potent antioxidant β-cells. By binding to GLP-1R, it activates the cAMP/
effects through the activation of the Nrf2 pathway, a master PKA and phospholipase C signaling pathways, leading
5,11
regulator of cellular redox homeostasis. Oxidative stress, to enhanced calcium influx and insulin granule
caused by an imbalance between reactive oxygen species exocytosis. This mechanism ensures a precise, nutrient-
(ROS) production and antioxidant defenses, is a major driven increase in insulin secretion without causing
contributor to neuronal damage and neurodegeneration. hypoglycemia. Simultaneously, GLP-1 suppresses glucagon
12
Both harmine and harmaline enhance the nuclear secretion from pancreatic α-cells, thereby reducing hepatic
translocation of Nrf2, which is normally sequestered in gluconeogenesis and further stabilizing blood glucose
the cytoplasm by its inhibitor, Kelch-like ECH-associated levels. 17
protein 1 (Keap1). 5,12 GLP-1 significantly amplifies the insulinotropic
Upon activation, Nrf2 dissociates from Keap1 and response by increasing the sensitivity of β-cells to glucose.
translocates to the nucleus, where it binds to antioxidant This effect is mediated by upregulating key transcription
response elements in the promoter regions of target genes. factors, such as pancreatic and duodenal homeobox 1,
13
This interaction leads to the upregulation of antioxidant which enhances the transcription and translation of
enzymes such as glutathione peroxidase, superoxide dismutase, insulin. 18
and catalase. By boosting the production of glutathione and In addition, GLP-1 promotes β-cell proliferation
neutralizing ROS, harmine and harmaline reduce oxidative and inhibits apoptosis, contributing to the long-term
damage to lipids, proteins, and DNA, thereby protecting preservation of pancreatic function, particularly in
neurons from oxidative stress-induced apoptosis. 5,14 conditions of metabolic stress such as type 2 diabetes mellitus
(T2DM). Beyond its effects on glucose metabolism,
19
An additional layer of molecular interaction exists
between the Akt and Nrf2 pathways, as harmine and GLP-1 plays a pivotal role in the regulation of appetite and
body weight. GLP-1R activation in the hypothalamus and
harmaline enhance Akt-mediated phosphorylation of brainstem modulates neuronal circuits involved in satiety
GSK-3β, an inhibitor of Nrf2. This phosphorylation and hunger. By activating pro-opiomelanocortin neurons
inactivates GSK-3β, preventing it from targeting Nrf2 for and inhibiting neuropeptide Y and agouti-related peptide
degradation. As a result, harmine and harmaline indirectly neurons, GLP-1 reduces food intake and increases feelings
amplify Nrf2 activity, creating a synergistic effect that of fullness. Furthermore, GLP-1 slows gastric emptying
20
strengthens antioxidant defenses while improving glucose through vagal afferent signaling, prolonging the presence
metabolism. 5,15
of nutrients in the gastrointestinal tract and enhancing
Through the coordinated regulation of the Akt/GLUT4 satiety signals. These effects collectively contribute to
and Nrf2 pathways, harmine and harmaline exhibit a dual reduced caloric intake and weight loss, making GLP-1
mechanism of action. They not only optimize neuronal analogs valuable therapeutic agents for obesity and its
glucose uptake and energy utilization but also alleviate associated metabolic dysfunctions. 21

Volume 2 Issue 3 (2025) 61 doi: 10.36922/IMO025060009