Potential role of IGF-1/GLP-1 signaling activation in intracerebral hemorrhage

Abstract

IGF-1 and GLP-1 receptors are essential in all tissues, facilitating defense by upregulating anabolic processes. They are abundantly distributed throughout the central nervous system, promoting neuronal proliferation, survival, and differentiation. IGF-1/GLP-1 is a growth factor that stimulates neurons' development, reorganization, myelination, and survival. In primary and secondary brain injury, the IGF-1/GLP-1 receptors are impaired, resulting in further neuro complications such as cerebral tissue degradation, neuroinflammation, oxidative stress, and atrophy. Intracerebral hemorrhage (ICH) is a severe condition caused by a stroke for which there is currently no effective treatment. While some pre-clinical studies and medications are being developed as symptomatic therapies in clinical trials, there are specific pharmacological implications for improving post-operative conditions in patients with intensive treatment. Identifying the underlying molecular process and recognizing the worsening situation can assist researchers in developing effective therapeutic solutions to prevent post-hemorrhagic symptoms and the associated neural dysfunctions. As a result, in the current review, we have addressed the manifestations of the disease that are aggravated by the downregulation of IGF-1 and GLP-1 receptors, which can lead to ICH or other neurodegenerative disorders. Our review summarizes that IGF-1/GLP-1 activators may be useful for treating ICH and its related neurodegeneration.

Keywords: GLP-1; IGF-1; Immune dysregulation; Intracerebral hemorrhage; Neuroprotection.

Graphical abstract

Fig. 1

Age-wise mortality incidences in brain hemorrhages.

Fig. 2

Clinical presentation during the progression of brain hemorrhage.

Fig. 3

Etiopathological hallmarks responsible for primary brain injury. Various etiopathological causes, such as trauma, stroke, aneurysm, etc., have affected different brain regions. Dysfunction in major brain areas leads to neuronal cell death, which further causes free radical generation, energy failure, hematoma development, etc. Primary brain injury occurs with the final activation of these cascades in the body.

Fig. 4

Consequences of secondary brain injury due to intracerebral hemorrhage. Another signaling cascade starts in the brain with the onset of primary brain injury, referred to as secondary brain injury. Additional neuro complications occur in the body throughout this phase, such as Nrf2 activation, fibrinogen, and thrombin, further contributing to neuroinflammation, edema, and microglia activation. Finally, these factors cause more severe tissue damage.

Fig. 5

Involvement of IGF-1/GLP-1 receptor signaling in various neurocomplications. The IGF-1 signal transduction on the growth axis mainly involves activating two signal transduction chains. The PI3K activation pathway and the MAPK activation pathway transmit mitotic and metabolic signals to the cell nucleus, activating IGF-1 secretion, inducing cell proliferation, differentiation, and inhibiting cell apoptosis. On the other hand, GLP-1R signaling facilitates β-cell glucose metabolism through PI3K-dependent activation of PKC and PDK. The GLP-1 receptor coupled with GLP-1R activates adenyl cyclase when it binds to GLP-1, increasing the cAMP's intracellular level. CAMP-mediated signaling promotes the RAP1A pathway, which, in turn, induces translational activation of BRAF, MEK, ERK, and thus promotes gene transcription, leading to neuroprotection. Abbreviations: IGF-1 = insulin like growth factor-1; GLP-1 = Glucagon like peptide-1; Ras = Rat sarcoma; Raf = Rapidly Accelerated Fibrosarcoma; IRS-1 = insulin receptor substrate-1; PIP2=Phosphatidylinositol 4,5-bisphosphate; PIP3 = phosphatidylinositol (3,4,5)-trisphosphate; PDK = 3-Phosphoinositide-dependent kinase; PI3k = 3-Phosphoinositide-dependent kinase 1; PKA = protein kinase A; PKB = protein kinase B; Akt = Ak strain transforming; mTOR = mammalian target of rapamycin; ROS = reactive oxygen species; GSK3-β = Glycogen synthase kinase 3-beta; MAPK = mitogen-activated protein kinase; MEK = Mitogen-activated protein kinase kinase; ERK = extracellular signal-regulated protein kinase; CREB = cAMP-response element binding protein; NF-kB = nuclear factor kappa-light-chain-enhancer of activated B cells; BCl-2=B-cell lymphoma 2; Bax = Bcl-2 Associated X-protein; Caspase = cysteine-dependent aspartate-directed proteases; AC = adenylyl cyclase; cAMP = cyclic Adenosine MonoPhosphate; GLUT4 = glucose transporter 4; ATP = Adenosine triphosphate; NOS = nitric oxide synthase.