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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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Phosphorylation-dephosphorylation mediated regulation of glycogen synthase kinase 3 β by serotonin and other cellular kinases. Serotonin type-1A (5-hydroxytryptamine [5-HT1A]) receptors activation by agonists as 8-hydroxy-N, N-dipropyl-2-aminotetralin inactivate the enzyme by phosphorylation at serine-9 residues through a series of cascade process involving protein kinase C (PKC), PKA, and Akt pathway, while antagonist (WAY100635) inhibit it. Serotonin type-2 (5-HT2) receptor agonists as 2, 5-dimethoxy-4-iodo-phenylisopropylamine by dephosphorylation activates the enzyme, while antagonists (LY53857) inhibit it[45]
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Figure 5: Phosphorylation-dephosphorylation mediated regulation of glycogen synthase kinase 3 β by serotonin and other cellular kinases. Serotonin type-1A (5-hydroxytryptamine [5-HT1A]) receptors activation by agonists as 8-hydroxy-N, N-dipropyl-2-aminotetralin inactivate the enzyme by phosphorylation at serine-9 residues through a series of cascade process involving protein kinase C (PKC), PKA, and Akt pathway, while antagonist (WAY100635) inhibit it. Serotonin type-2 (5-HT2) receptor agonists as 2, 5-dimethoxy-4-iodo-phenylisopropylamine by dephosphorylation activates the enzyme, while antagonists (LY53857) inhibit it[45]

Mentions: Another major cellular mechanism that can suggest the arousal of depressive symptoms in diabetic individuals is the glycogen synthase kinase 3 (GSK3) pathway and the regulatory influence of 5-HT system on GSK3. GSK3 has been known to exert significant influences on the neuronal plasticity, cellular architecture as well as regulation of apoptosis and cell survival.[43] GSK3 is basically a cytosolic serine/threonine protein kinase with two isoforms α/β which arrest glycogen synthesis as one of its regulatory processes by inhibiting the rate-limiting enzyme glycogen synthase. Several metabolic disorders like diabetes are associated with an increased GSK3 expression, and GSK3 mediated multifunctional process may add on the neuropsychiatric complications such as depression to be associated with diabetes. The phosphorylation and dephosphorylation mechanisms are the most studied regulatory process of GSK3 [Figure 5]. The α and β isoforms of GSK are inhibited by phosphorylation of an N-terminal serine (serine-9 in GSK3 β and serine-21 in GSK3α) that can be mediated by a number of different kinases including protein kinase A (PKA), protein kinase Cand Akt.[44] This phosphorylation mediated inhibition of GSK is found to be impaired in diabetes which can have a profound impact on the neuronal plasticity and neurogenesis, culminating in neuropsychiatric disorders like depression. Another interesting finding is the association of the 5-HT activity with inhibitory control of GSK3 expression. It has been identified that stimulation of 5-HT1A receptors and antagonism of 5-HT2A receptors can increase the serine-9 mediated phosphorylation of GSK3 β, indicating a dynamic regulatory balance between the two 5-HT receptors in the brain.[45] The 5-HT1A receptors coupled to Gi can activate the PI3K and Akt, which in turn can trigger the phosphorylation of GSK3 β. Interestingly the brain samples from depressed suicide victims indicated a suppressed activity of PI3K and Akt that may account for the higher GSK3 β activity that might have led to depression.[46] Though there is no conclusive report, 5-HT2A receptors are classically coupled with Gq and may involve PLC/PKC signaling mechanism mediated regulation of GSK3.[47] An increased uncontrolled expression of GSK3 in diabetes may reflect the impaired regulatory effect of 5-HT system leading to depression-like condition in diabetes patients.


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)

Phosphorylation-dephosphorylation mediated regulation of glycogen synthase kinase 3 β by serotonin and other cellular kinases. Serotonin type-1A (5-hydroxytryptamine [5-HT1A]) receptors activation by agonists as 8-hydroxy-N, N-dipropyl-2-aminotetralin inactivate the enzyme by phosphorylation at serine-9 residues through a series of cascade process involving protein kinase C (PKC), PKA, and Akt pathway, while antagonist (WAY100635) inhibit it. Serotonin type-2 (5-HT2) receptor agonists as 2, 5-dimethoxy-4-iodo-phenylisopropylamine by dephosphorylation activates the enzyme, while antagonists (LY53857) inhibit it[45]
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Phosphorylation-dephosphorylation mediated regulation of glycogen synthase kinase 3 β by serotonin and other cellular kinases. Serotonin type-1A (5-hydroxytryptamine [5-HT1A]) receptors activation by agonists as 8-hydroxy-N, N-dipropyl-2-aminotetralin inactivate the enzyme by phosphorylation at serine-9 residues through a series of cascade process involving protein kinase C (PKC), PKA, and Akt pathway, while antagonist (WAY100635) inhibit it. Serotonin type-2 (5-HT2) receptor agonists as 2, 5-dimethoxy-4-iodo-phenylisopropylamine by dephosphorylation activates the enzyme, while antagonists (LY53857) inhibit it[45]
Mentions: Another major cellular mechanism that can suggest the arousal of depressive symptoms in diabetic individuals is the glycogen synthase kinase 3 (GSK3) pathway and the regulatory influence of 5-HT system on GSK3. GSK3 has been known to exert significant influences on the neuronal plasticity, cellular architecture as well as regulation of apoptosis and cell survival.[43] GSK3 is basically a cytosolic serine/threonine protein kinase with two isoforms α/β which arrest glycogen synthesis as one of its regulatory processes by inhibiting the rate-limiting enzyme glycogen synthase. Several metabolic disorders like diabetes are associated with an increased GSK3 expression, and GSK3 mediated multifunctional process may add on the neuropsychiatric complications such as depression to be associated with diabetes. The phosphorylation and dephosphorylation mechanisms are the most studied regulatory process of GSK3 [Figure 5]. The α and β isoforms of GSK are inhibited by phosphorylation of an N-terminal serine (serine-9 in GSK3 β and serine-21 in GSK3α) that can be mediated by a number of different kinases including protein kinase A (PKA), protein kinase Cand Akt.[44] This phosphorylation mediated inhibition of GSK is found to be impaired in diabetes which can have a profound impact on the neuronal plasticity and neurogenesis, culminating in neuropsychiatric disorders like depression. Another interesting finding is the association of the 5-HT activity with inhibitory control of GSK3 expression. It has been identified that stimulation of 5-HT1A receptors and antagonism of 5-HT2A receptors can increase the serine-9 mediated phosphorylation of GSK3 β, indicating a dynamic regulatory balance between the two 5-HT receptors in the brain.[45] The 5-HT1A receptors coupled to Gi can activate the PI3K and Akt, which in turn can trigger the phosphorylation of GSK3 β. Interestingly the brain samples from depressed suicide victims indicated a suppressed activity of PI3K and Akt that may account for the higher GSK3 β activity that might have led to depression.[46] Though there is no conclusive report, 5-HT2A receptors are classically coupled with Gq and may involve PLC/PKC signaling mechanism mediated regulation of GSK3.[47] An increased uncontrolled expression of GSK3 in diabetes may reflect the impaired regulatory effect of 5-HT system leading to depression-like condition in diabetes patients.

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