Oxidative stress injury and glucolipotoxicity in type 2 diabetes mellitus: The potential role of metformin and sitagliptin

Abdul-Hadi, May Hassan; Naji, Marwa Thaier; Shams, Hala Akeel; Sami, Oula Mohamed; Al-Harchan, Naseer Abdul-Amer; Al-Kuraishy, Hayder M; Al-Gareeb, Ali I

doi:10.4103/bbrj.bbrj_7_20

Cited by 25 publications

(8 citation statements)

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“…It has been reported that T2DM patients have a 50%–75% risk of AD development, and AD patients have a higher risk of developing T2DM 72,73 . Data from clinical studies support the use of NEP inhibitors in the prevention and treatment of T2DM 74,75 .…”

Section: Mechanistic Role Of Nep Inhibitors In Admentioning

confidence: 95%

Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective

Ali,

Al‐Kuraishy,

Al‐Gareeb

et al. 2023

J Cellular Molecular Medi

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Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease with multifaceted neuropathological disorders. AD is characterized by intracellular accumulation of phosphorylated tau proteins and extracellular deposition of amyloid beta (Aβ). Various protease enzymes, including neprilysin (NEP), are concerned with the degradation and clearance of Aβ. Indeed, a defective neuronal clearance pathway due to the dysfunction of degradation enzymes might be a possible mechanism for the accumulation of Aβ and subsequent progression of AD neuropathology. NEP is one of the most imperative metalloproteinase enzymes involved in the clearance of Aβ. This review aimed to highlight the possible role of NEP inhibitors in AD. The combination of sacubitril and valsartan which is called angiotensin receptor blocker and NEP inhibitor (ARNI) may produce beneficial and deleterious effects on AD neuropathology. NEP inhibitors might increase the risk of AD by the inhibition of Aβ clearance, and increase brain bradykinin (BK) and natriuretic peptides (NPs), which augment the pathogenesis of AD. These verdicts come from animal model studies, though they may not be applied to humans. However, clinical studies revealed promising safety findings regarding the use of ARNI. Moreover, NEP inhibition increases various neuroprotective peptides involved in inflammation, glucose homeostasis and nerve conduction. Also, NEP inhibitors may inhibit dipeptidyl peptidase 4 (DPP4) expression, ameliorating insulin and glucagon‐like peptide 1 (GLP‐1) levels. These findings proposed that NEP inhibitors may have a protective effect against AD development by increasing GLP‐1, neuropeptide Y (NPY) and substance P, and deleterious effects by increasing brain BK. Preclinical and clinical studies are recommended in this regard.

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Section: Mechanistic Role Of Nep Inhibitors In Admentioning

confidence: 95%

Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective

Ali,

Al‐Kuraishy,

Al‐Gareeb

et al. 2023

J Cellular Molecular Medi

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show abstract

“…165 The mitochondria are the major site for the generation of ROS, which affect mitochondrial DNA, leading to more ROS generation. 166 Notably, the brain is extremely vulnerable to the effects of oxidative stress due to advanced metabolic activity, the generation of ROS, and its lower antioxidant capacity. 167 Chronic stressful condition in depression encourages oxidative stress and mitochondrial dysfunction.…”

Section: Ras Mitochondrial Dysfunction and Oxidative Stressmentioning

confidence: 99%

“…When there is an imbalance between ROS generation and antioxidant capacity, oxidative stress is developed 165 . The mitochondria are the major site for the generation of ROS, which affect mitochondrial DNA, leading to more ROS generation 166 . Notably, the brain is extremely vulnerable to the effects of oxidative stress due to advanced metabolic activity, the generation of ROS, and its lower antioxidant capacity 167 .…”

Section: Mechanistic Role Of Brain Ras In Depressionmentioning

confidence: 99%

Role of brain renin–angiotensin system in depression: A new perspective

Ali,

Al‐Kuraishy,

Al‐Gareeb

et al. 2023

CNS Neurosci Ther

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Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression is related to the deficiency of serotonin (5HT), which is derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of depression. Notably, the renin–angiotensin system (RAS) is involved in the pathogenesis of depression, and different findings revealed that angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may be effective in depression. However, the underlying mechanism for the role of dysregulated brain RAS‐induced depression remains speculative. Therefore, this review aimed to revise the conceivable role of ACEIs and ARBs and how these agents ameliorate the pathophysiology of depression. Dysregulation of brain RAS triggers the development and progression of depression through the reduction of brain 5HT and expression of brain‐derived neurotrophic factor (BDNF) and the induction of mitochondrial dysfunction, oxidative stress, and neuroinflammation. Therefore, inhibition of central classical RAS by ARBS and ACEIs and activation of non‐classical RAS prevent the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation.

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“…These findings highlighted a positive feedback loop between T2D and epilepsy. In this state, treatment of T2D patients by metformin decreases hyperglycaemia and cardiometabolic complications which are comorbid risk factors for the development of epilepsy 56,57 . Also, metformin attenuates brain IR which is associated with the severity of seizure 58,59 .…”

Section: The Mechanistic Role Of Metformin In Epilepsymentioning

confidence: 99%

“…In this state, treatment of T2D patients by metformin decreases hyperglycaemia and cardiometabolic complications which are comorbid risk factors for the development of epilepsy. 56,57 Also, metformin attenuates brain IR which is associated with the severity of seizure. 58,59 Central IR is regarded as a possible connection between T2D and epilepsy as well as neurodegenerative disorders such as Alzheimer's disease (AD).…”

Section: Metformin Mitigates Diabetes-epilepsy Loopmentioning

confidence: 99%

New insights on the potential anti‐epileptic effect of metformin: Mechanistic pathway

Alnaaim,

Al‐kuraishy,

Al‐Gareeb

et al. 2023

J Cellular Molecular Medi

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Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well‐controlled disease by anti‐epileptic agents (AEAs) in about 69%. However, 30%–40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA‐approved drugs that have an anti‐seizure activity to the anti‐epileptic regimen is logical. The anti‐diabetic agent metformin has anti‐seizure activity. Nevertheless, the underlying mechanism of the anti‐seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti‐seizure activity by triggering adenosine monophosphate‐activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain‐derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti‐seizure mechanism of metformin. Also, metformin reduces α‐synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard.

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Oxidative stress injury and glucolipotoxicity in type 2 diabetes mellitus: The potential role of metformin and sitagliptin

Cited by 25 publications

References 0 publications

Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective

Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective

Role of brain renin–angiotensin system in depression: A new perspective

New insights on the potential anti‐epileptic effect of metformin: Mechanistic pathway

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