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

1. Introduction history in traditional medicine, and the stimulation of
GLP-1 secretion. Given the pharmacological significance
Glucagon-like peptide-1 (GLP-1) is an incretin hormone of GLP-1 as a key regulator of glucose metabolism and
secreted by enteroendocrine L-cells in the distal small its emerging role in metabolic and neurodegenerative
intestine and colon in response to nutrient ingestion, disorders, identifying natural agents capable of enhancing
particularly carbohydrates and lipids. At the molecular GLP-1 secretion has garnered considerable scientific
level, GLP-1 exerts its effects through the GLP-1 receptor interest. P. harmala, known for its bioactive alkaloids,
(GLP-1R), a G-protein-coupled receptor widely expressed including harmine and harmaline, has demonstrated
in pancreatic β-cells, the central nervous system, and diverse metabolic and neuroprotective properties that may
peripheral tissues. Upon binding to its receptor, GLP-1 intersect with GLP-1 pathways. By examining existing
1
activates the cAMP/protein kinase A (PKA) signaling evidence, this review seeks to provide a comprehensive
pathway, leading to enhanced glucose-stimulated insulin overview of the molecular and biological mechanisms
secretion, inhibition of glucagon release, and delayed
gastric emptying. These actions collectively improve post- through which the herb’s influence on GLP-1 secretion. In
prandial glucose homeostasis, making GLP-1 a critical addition, the implications of this interaction in developing
regulator of metabolic processes. 2 novel therapeutic strategies for diabetes, obesity, and related
metabolic dysfunctions are highlighted. This synthesis
In addition to its metabolic effects, GLP-1 demonstrates aims to bridge the gap between traditional medicine and
significant neuroprotective properties. Its receptor contemporary scientific research, paving the way for future
activation in the brain enhances neuronal survival, reduces investigations into the therapeutic potential of P. harmala
oxidative stress, and inhibits neuroinflammatory pathways in modulating GLP-1 activity.
through modulation of intracellular signaling cascades
such as phosphoinositide 3-kinase (PI3K)/Akt and 2. Present evidence on the effects of P. harmala on the
MAPK. These properties have positioned GLP-1 analogs brain
3
as promising therapeutic agents for neurodegenerative Recent studies have shed light on the neurotherapeutic
disorders, including Alzheimer’s disease (AD) and potential of P. harmala, particularly in enhancing GLP-1
Parkinson’s disease. Furthermore, GLP-1’s ability to levels in the brain and improving central insulin sensitivity.
suppress appetite and promote weight loss highlights its In a pre-clinical model of AD, P. harmala seed extract
role in addressing obesity-related metabolic dysfunctions. 4 demonstrated significant efficacy in countering AD-related
Peganum harmala, commonly known as harmal or Syrian neurodegeneration, particularly within the hippocampus,
rue, has been extensively utilized in traditional medicine a critical region for memory and cognition. The extract
across various cultures for its therapeutic properties, increased hippocampal GLP-1 and insulin levels while
particularly in the management of neurological disorders. reducing insulin receptor substrate-1 phosphorylation
Historically, harmal has been employed as a remedy for at serine 307 (pS307-IRS-1), a key marker of insulin
conditions such as epilepsy, anxiety, and insomnia due to resistance. These findings highlight the ability of P. harmala
its notable psychoactive and neuroprotective effects. The to enhance insulin signaling through the activation of
medicinal potential of harmal is attributed to its bioactive Akt phosphorylation at serine 473 (pS473-Akt) and
alkaloids, primarily harmine, and harmaline, which belong upregulation of glucose transporter type 4 (GLUT4).
to the β-carboline class of compounds. 5 In addition to modulating insulin pathways, P. harmala
Harmine and harmaline exert their effects through reduced the accumulation of pathological markers associated
multiple molecular mechanisms, including monoamine with AD, including beta-amyloid (Aβ42), phosphorylated
oxidase inhibition, which elevates neurotransmitter levels tau, and glycogen synthase kinase-3β (GSK-3β). These effects
such as serotonin, dopamine, and norepinephrine in the were further augmented by the activation of the nuclear factor
central nervous system. This activity underpins harmal’s erythroid 2-related factor 2 (Nrf2) antioxidant pathway,
antidepressant and anxiolytic properties. In addition, leading to reduced oxidative stress and replenishment of
these alkaloids modulate GABAergic and glutamatergic hippocampal glutathione levels. Collectively, these molecular
pathways, contributing to their anticonvulsant effects. mechanisms underline the dual role of P. harmala in
Recent studies have also highlighted their neuroprotective mitigating insulin resistance and enhancing GLP-1 signaling,
potential, which is realized by reducing oxidative stress and which synergistically improves neuronal glucose uptake and
inflammation, as well as promoting neuronal regeneration. 6 reduces the burden of amyloid pathology in the brain. 7
This perspective aims to explore the potential Harmine and harmaline, the primary bioactive alkaloids
relationship between P. harmala, a plant with a rich in P. harmala, modulate key signaling cascades involved

Volume 2 Issue 3 (2025) 60 doi: 10.36922/IMO025060009