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Diabetes-associated depression: the serotonergic system as a novel multifunctional target.

Prabhakar V, Gupta D, Kanade P, Radhakrishnan M - Indian J Pharmacol (2015 Jan-Feb)

Bottom Line: Persisting hyperglycemia leads to impaired neurogenesis, decreased synaptic plasticity, undesired neuro-anatomical alterations, neurochemical deficits, and reduced neurotransmitter activity.The neurotrophic factors and secondary messenger functions affected at molecular and genetic levels indicate the impact of diabetes-mediated dysregulation on neuronal circuits.HPA activity, glycogen synthase kinase 3, and insulin signaling controls were also found to be hampered, interlinked to 5-HT system following diabetic progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy and, Birla Institute of Technology and Science, Pilani, Rajasthan, India.

ABSTRACT
Diabetes associated depression is a largely understudied field which nonetheless carries a significant disease burden. The very low therapeutic efficacy of the existing conventional drugs with poor outcome may be, in part, due to uncertainty of the mechanism involved that clearly explains the existing comorbidity. The main purpose of this review was to address the sophisticated mechanisms of this comorbidity with a view of developing potential novel targets with higher efficacy and specificity. Data were collected from database searches including PubMed, references from relevant English language research/review articles and other official publications. Articles from 1990 to 2013 were included, and a broad search term criteria were followed for data mining so that relevant information was not missed out. Some of the search terms used included; diabetes-induced depression, diabetes and serotonin, hypothalamic-pituitary-adrenal (HPA) axis and diabetes and glucocorticoids in diabetes. Neuropathologically, depletion of brain monoaminergic activity specifically the serotonin (5-hydroxytryptamine [5-HT]) system, due to chronically persisting diabetic state may lead to the mood and behavioral complications that further add on worsening the quality life years. The 5-HT system through multifunctional tasks regulates neurogenesis and plasticity and by complex receptor mechanism controls the emotional and behavioral activity. Persisting hyperglycemia leads to impaired neurogenesis, decreased synaptic plasticity, undesired neuro-anatomical alterations, neurochemical deficits, and reduced neurotransmitter activity. The neurotrophic factors and secondary messenger functions affected at molecular and genetic levels indicate the impact of diabetes-mediated dysregulation on neuronal circuits. HPA activity, glycogen synthase kinase 3, and insulin signaling controls were also found to be hampered, interlinked to 5-HT system following diabetic progression.

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Glucocorticoids (GCs) mediated regulation of brain-derived neurotrophic factors (BDNF) transcription. GCs alter the transcription in nucleus and ribosomal translation process of BDNF and hence affect its synthesis. mRNA= micro RNA[67]
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Figure 2: Glucocorticoids (GCs) mediated regulation of brain-derived neurotrophic factors (BDNF) transcription. GCs alter the transcription in nucleus and ribosomal translation process of BDNF and hence affect its synthesis. mRNA= micro RNA[67]

Mentions: Another major link between diabetes and depression is the alteration in the neurotrophic mechanisms including suppression of the brain-derived neurotrophic factor (BDNF) possibly by pathways that involve GC excess. The regulation of BDNF and other similar neuropeptides by GCs has been well-established and can take place through a variety of cellular pathways.[36] Furthermore, BDNF and other neuropeptides have been found to be involved in the regulation of 5-HT system.[37] One of the most direct involvements of the GC in BDNF regulation is the modulation of BDNF transcription by binding of GC on the glucocorticoid response element in the promoter regions. Another mechanism is the interference in the proteolytic conversion of pro-BDNF to mature-BDNF thereby altering the levels of matured BDNF in the brain [Figure 2]. Further, the binding of BDNF to its tyrosine kinases B leads to activation of phospholipase C-γ (PLC-γ), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinase pathways leading to downstream activation resulting in many physiological process including synaptic plasticity, neuronal excitability, and survival [Figure 3]. The GCs have been found to regulate these pathways at multiple points resulting in the overall depression of BDNF activity.[38]


Diabetes-associated depression: the serotonergic system as a novel multifunctional target.

Prabhakar V, Gupta D, Kanade P, Radhakrishnan M - Indian J Pharmacol (2015 Jan-Feb)

Glucocorticoids (GCs) mediated regulation of brain-derived neurotrophic factors (BDNF) transcription. GCs alter the transcription in nucleus and ribosomal translation process of BDNF and hence affect its synthesis. mRNA= micro RNA[67]
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4375817&req=5

Figure 2: Glucocorticoids (GCs) mediated regulation of brain-derived neurotrophic factors (BDNF) transcription. GCs alter the transcription in nucleus and ribosomal translation process of BDNF and hence affect its synthesis. mRNA= micro RNA[67]
Mentions: Another major link between diabetes and depression is the alteration in the neurotrophic mechanisms including suppression of the brain-derived neurotrophic factor (BDNF) possibly by pathways that involve GC excess. The regulation of BDNF and other similar neuropeptides by GCs has been well-established and can take place through a variety of cellular pathways.[36] Furthermore, BDNF and other neuropeptides have been found to be involved in the regulation of 5-HT system.[37] One of the most direct involvements of the GC in BDNF regulation is the modulation of BDNF transcription by binding of GC on the glucocorticoid response element in the promoter regions. Another mechanism is the interference in the proteolytic conversion of pro-BDNF to mature-BDNF thereby altering the levels of matured BDNF in the brain [Figure 2]. Further, the binding of BDNF to its tyrosine kinases B leads to activation of phospholipase C-γ (PLC-γ), phosphatidylinositol-3-kinase (PI3K), and mitogen-activated protein kinase pathways leading to downstream activation resulting in many physiological process including synaptic plasticity, neuronal excitability, and survival [Figure 3]. The GCs have been found to regulate these pathways at multiple points resulting in the overall depression of BDNF activity.[38]

Bottom Line: Persisting hyperglycemia leads to impaired neurogenesis, decreased synaptic plasticity, undesired neuro-anatomical alterations, neurochemical deficits, and reduced neurotransmitter activity.The neurotrophic factors and secondary messenger functions affected at molecular and genetic levels indicate the impact of diabetes-mediated dysregulation on neuronal circuits.HPA activity, glycogen synthase kinase 3, and insulin signaling controls were also found to be hampered, interlinked to 5-HT system following diabetic progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy and, Birla Institute of Technology and Science, Pilani, Rajasthan, India.

ABSTRACT
Diabetes associated depression is a largely understudied field which nonetheless carries a significant disease burden. The very low therapeutic efficacy of the existing conventional drugs with poor outcome may be, in part, due to uncertainty of the mechanism involved that clearly explains the existing comorbidity. The main purpose of this review was to address the sophisticated mechanisms of this comorbidity with a view of developing potential novel targets with higher efficacy and specificity. Data were collected from database searches including PubMed, references from relevant English language research/review articles and other official publications. Articles from 1990 to 2013 were included, and a broad search term criteria were followed for data mining so that relevant information was not missed out. Some of the search terms used included; diabetes-induced depression, diabetes and serotonin, hypothalamic-pituitary-adrenal (HPA) axis and diabetes and glucocorticoids in diabetes. Neuropathologically, depletion of brain monoaminergic activity specifically the serotonin (5-hydroxytryptamine [5-HT]) system, due to chronically persisting diabetic state may lead to the mood and behavioral complications that further add on worsening the quality life years. The 5-HT system through multifunctional tasks regulates neurogenesis and plasticity and by complex receptor mechanism controls the emotional and behavioral activity. Persisting hyperglycemia leads to impaired neurogenesis, decreased synaptic plasticity, undesired neuro-anatomical alterations, neurochemical deficits, and reduced neurotransmitter activity. The neurotrophic factors and secondary messenger functions affected at molecular and genetic levels indicate the impact of diabetes-mediated dysregulation on neuronal circuits. HPA activity, glycogen synthase kinase 3, and insulin signaling controls were also found to be hampered, interlinked to 5-HT system following diabetic progression.

Show MeSH
Related in: MedlinePlus