The developing CNS: a scenario for the action of proinsulin, insulin and insulin-like growth factors

doi:10.1016/0166-2236(95)93892-2

Trends in Neurosciences

Volume 18, Issue 3, March 1995, Pages 143-150

https://doi.org/10.1016/0166-2236(95)93892-2 Get rights and content

Abstract

The multifunctional cytokines of the family of insulin and insulin-like growth factors (IGFs) have not yet gained general recognition as essential cell signals for the development of the vertebrate nervous system. This is, in part, a consequence of previous constraints in our thinking, focused for many years on the endocrine roles of these factors in late mammalian development and postnatal stages. The cellular distribution of the components of the insulin and IGFs signalling system in the developing mammalian and avian CNS is remarkably conserved. While receptors are widespread, the much less abundant factors and modulatory proteins are highly regulated in time and space. Progression of neural development through the steps of cell proliferation, differentiation, maturation and survival is stimulated, at least in culture, by proinsulin and insulin and the IGFs. Thus, these factors might be important autocrine and paracrine signals during development of the CNS.

References (88)

P.H. Patterson et al.
Cell
(1993)
P.H. Patterson et al.
Neuron
(1993)
S. Korshing
J. Neurosci.
(1993)
R.G.D. Milner et al.
Eur. J. Pediatr.
(1987)
M.F. White et al.
J. Biol. Chem.
(1994)
M.M. Rechler
Vitam. Horm.
(1993)
D.G. Baskin
Endocrinology
(1994)
S.J. Giddings
Nature Genet.
(1994)
D.G. Baskin
Trends Neurosci.
(1988)
S. Gammeltoft
H. Werner

F. De Pablo et al.

Endocr. Rev.

(1990)

S.U. Devaskar

J. Biol. Chem.

(1994)

F. de Pablo

Endocrinology

(1982)

E.J. de la Rosa

Eur. J. Neurosci.

(1994)

D.G. Meimaridis

Neurosci. Lett.

(1990)

F. Stylianopoulou

Development

(1988)

R.D. Streck et al.

Endocrinology

(1992)

T.L. Wood

Mol. Endocrinol.

(1990)

F.C. Nielsen et al.

J. Neurochem.

(1991)

S. Ghaskadbi et al.

Int. J. Dev. Biol.

(1993)

J. Shemer

J. Biol. Chem.

(1987)

F.A. McMorris et al.

J. Neurosci. Res.

(1988)

C.D. Toran-Allerand

Brain Res.

(1991)

I. Torres-Alemán et al.

Eur. J. Neurosci.

(1992)

K.A. Heidenreich

J. Biol. Chem.

(1990)

J. Drago

A.B. Smit

Nature

(1988)

M.C. Raff

Science

(1993)

R.M. Lindsay

Trends Neurosci.

(1994)

J. Schlessinger et al.

Neuron

(1992)

S. Kornfeld

Annu. Rev. Biochem.

(1992)

J.L. Treadway

M.A. Soos et al.

Biochem. J.

(1993)

M.K. Raizada

Endocrinology

(1993)

P.-J. Liu

Cell

(1993)

F. De Pablo et al.

Trends Biochem. Sci.

(1990)

T.M. DeChiara et al.

Cell

(1991)

W.H. Daughaday et al.

Endocr. Rev.

(1989)

K.A. Heidenreich

Trends Endocrinol. Metab.

(1991)

D. LeRoith

Ann. NY Acad. Sci.

(1993)

M. Wozniak

Neurochem. Int.

(1993)

L. Deltour

S.U. Devaskar

Regul. Peptides

(1993)

J. Serrano

Develop. Biol.

(1989)

Cited by (229)

Exploring structural determinants of neuroprotection bias on novel glypromate conjugates with bioactive amines
2024, European Journal of Medicinal Chemistry
Neurodegenerative disorders of the central nervous system (CNS) such as Alzheimer's and Parkinson's diseases, afflict millions globally, posing a significant public health challenge. Despite extensive research, a critical hurdle in effectively treating neurodegenerative diseases is the lack of neuroprotective drugs that can halt or reverse the underlying disease processes. In this work, we took advantage of the neuroprotective properties of the neuropeptide glycyl-l-prolyl-l-glutamic acid (Glypromate) for the development of new peptidomimetics using l-pipecolic acid as a proline surrogate and exploring their chemical conjugation with relevant active pharmaceutical ingredients (API) via a peptide bond. Together with prolyl-based Glypromate conjugates, a total of 36 conjugates were toxicologically and biologically evaluated. In this series, the results obtained showed that a constrained ring (l-proline) at the central position of the peptide motif accounts for enhanced toxicological profiles and biological effects using undifferentiated and differentiated human neuroblastoma SH-SY5Y cells. Additionally, it was shown that biased biological responses are API-dependent. Conjugation with (R)-1-aminoindane led to a 38–43% reduction of protein aggregation induced by Aβ_25-35 (10 μM), denoting a 3.2–3.6-fold improvement in comparison with the parent neuropeptide, with no significative difference between functionalization at α and γ-carboxyl ends. On the other hand, the best-performing neuroprotective conjugate against the toxicity elicited by 6-hydroxydopamine (6-OHDA, 125 μM) was obtained by conjugation with memantine at the α-carboxyl end, resulting in a 2.3-fold improvement of the neuroprotection capacity in comparison with Glypromate neuropeptide. Altogether, the chemical strategy explored in this work shows that the neuroprotective capacity of Glypromate can be modified and fine-tuned, opening a new avenue for the development of biased neurotherapeutics for CNS-related disorders.
Growth factors and their receptors: multitasking functionality in health and disease
2023, Receptor Tyrosine Kinases in Neurodegenerative and Psychiatric Disorders
Growth factors play critical roles in the growth and maintenance of the nervous system. Their robust survival and functional capacities make them the “powerhouse” in both physiological and pathological processes in the peripheral and central nervous systems. Indeed, it has been proposed that the aberration in the expressions of the growth factors played significant roles in the pathogenesis of neurodegenerative diseases and psychiatric disorders, which makes them ideal therapeutic options. Despite the great interest in employing growth factors to prevent and/or mitigate the neurodegeneration and atrophy observed in experiments on these diseases, considerable challenges remain. Therefore, this chapter examines the role of growth factor members that bind to receptor tyrosine kinase and their partaking in neurodegeneration and provides roadmaps for future translational research.
Neurodegenerative diseases and effective drug delivery: A review of challenges and novel therapeutics
2021, Journal of Controlled Release
Citation Excerpt :
It also has tendency to block both necrotic and apoptotic cells death, by activating PI-3/Akt kinases pathways [99]. Tumor promoting capacity of this growth factor could be minimized by utilization low doses for longer duration of time [100]. The drug development for ND diseases is a high-risk therapeutic area where only 12% of all the drug candidates that are subjected to clinical trials, got approval for human use.
The central nervous system (CNS) encompasses the brain and spinal cord and is considered the processing center and the most vital part of human body. The central nervous system (CNS) barriers are crucial interfaces between the CNS and the periphery. Among all these biological barriers, the blood-brain barrier (BBB) strongly impede hurdle for drug transport to brain. It is a semi-permeable diffusion barrier against the noxious chemicals and harmful substances present in the blood stream and regulates the nutrients delivery to the brain for its proper functioning. Neurological diseases owing to the existence of the BBB and the blood-spinal cord barrier have been terrible and threatening challenges all over the world and can rarely be directly mediated. In fact, drug delivery to brain remained a challenge in the treatment of neurodegenerative (ND) disorders, for these different approaches have been proposed. Nano-fabricated smart drug delivery systems and implantable drug loaded biomaterials for brain repair are among some of these latest approaches. In current review, modern approaches developed to deal with the challenges associated with transporting drugs to the CNS are included. Recent studies on neural drug discovery and injectable hydrogels provide a potential new treatment option for neurological disorders. Moreover, induced pluripotent stem cells used to model ND diseases are discussed to evaluate drug efficacy. These protocols and recent developments will enable discovery of more effective drug delivery systems for brain.
Proinsulin protects against age-related cognitive loss through anti-inflammatory convergent pathways
2017, Neuropharmacology
Brain inflammaging is increasingly considered as contributing to age-related cognitive loss and neurodegeneration. Despite intensive research in multiple models, no clinically effective pharmacological treatment has been found yet. Here, in the mouse model of brain senescence SAMP8, we tested the effects of proinsulin, a promising neuroprotective agent that was previously proven to be effective in mouse models of retinal neurodegeneration. Proinsulin is the precursor of the hormone insulin but also upholds developmental physiological effects, particularly as a survival factor for neural cells. Adeno-associated viral vectors of serotype 1 bearing the human proinsulin gene were administered intramuscularly to obtain a sustained release of proinsulin into the blood stream, which was able to reach the target area of the hippocampus. SAMP8 mice and the control strain SAMR1 were treated at 1 month of age. At 6 months, behavioral testing exhibited cognitive loss in SAMP8 mice treated with the null vector. Remarkably, the cognitive performance achieved in spatial and recognition tasks by SAMP8 mice treated with proinsulin was similar to that of SAMR1 mice. In the hippocampus, proinsulin induced the activation of neuroprotective pathways and the downstream signaling cascade, leading to the decrease of neuroinflammatory markers. Furthermore, the decrease of astrocyte reactivity was a central effect, as demonstrated in the connectome network of changes induced by proinsulin. Therefore, the neuroprotective effects of human proinsulin unveil a new pharmacological potential therapy in the fight against cognitive loss in the elderly.
Neural Stem Cell-based Regenerative Therapy: A New Approach to Diabetes Treatment
2024, Endocrine, Metabolic and Immune Disorders - Drug Targets
Exploring Structural Determinants of Neuroprotection Bias on Novel Glypromate Bioconjugates with Bioactive Amines
2023, SSRN

View all citing articles on Scopus

View full text

Trends in Neurosciences

ReviewThe developing CNS: a scenario for the action of proinsulin, insulin and insulin-like growth factors

Abstract

Cell

Neuron

J. Neurosci.

Eur. J. Pediatr.

J. Biol. Chem.

Vitam. Horm.

Endocrinology

Nature Genet.

Trends Neurosci.

Endocr. Rev.

J. Biol. Chem.

Endocrinology

Eur. J. Neurosci.

Neurosci. Lett.

Development

Endocrinology

Mol. Endocrinol.

J. Neurochem.

Int. J. Dev. Biol.

J. Biol. Chem.

J. Neurosci. Res.

Brain Res.

Eur. J. Neurosci.

J. Biol. Chem.

Nature

Science

Trends Neurosci.

Neuron

Annu. Rev. Biochem.

Biochem. J.

Endocrinology

Cell

Trends Biochem. Sci.

Cell

Endocr. Rev.

Trends Endocrinol. Metab.

Ann. NY Acad. Sci.

Neurochem. Int.

Regul. Peptides

Develop. Biol.

Review
The developing CNS: a scenario for the action of proinsulin, insulin and insulin-like growth factors