Intranasal insulin and orexins to treat age-related cognitive decline

Erichsen, Jennifer; Calva, Coleman B.; Reagan, Lawrence P.; Fadel, Jim R.

doi:10.1016/j.physbeh.2021.113370

Cited by 21 publications

(14 citation statements)

References 279 publications

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“…A majority of these studies provided evidence that the IN insulin is safe and well tolerated while revealing a great potential for memory-enhancing and/ or memory-preserving effects (Schmid et al, 2018). These studies also showed that several factors, including insulin formulation, length of treatment, sex, dose, and APOE genotype, affect the treatment response (Avgerinos et al, 2018;Erichsen et al, 2021;Hallschmid, 2021a,b). Preclinical studies in rodent models corroborated human studies.…”

Section: Therapeutic Targets Insulinmentioning

confidence: 99%

“…This leads to regulation of transcription factors, such as FOXO1, and subsequent transcription of genes involved in key functions in neurons and glia. In addition, Akt can inhibit glycogen synthase kinase 3β (GSK3β), a constitutively active enzyme that not only regulates glycogen synthase but also promotes microtubule-associated tau protein phosphorylation, which contributes to neurofibrillary tangle formation in neurodegenerative diseases ( Erichsen et al, 2021 ; Scherer et al, 2021 ). The lack of these central effects of insulin, either due to poor transport into brain or impaired insulin signaling, lead to many metabolic abnormalities.…”

Section: Therapeutic Targetsmentioning

confidence: 99%

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Novel Targets and Interventions for Cognitive Complications of Diabetes

2022

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Diabetes and cognitive dysfunction, ranging from mild cognitive impairment to dementia, often coexist in individuals over 65 years of age. Vascular contributions to cognitive impairment/dementia (VCID) are the second leading cause of dementias under the umbrella of Alzheimer’s disease and related dementias (ADRD). Over half of dementia patients have VCID either as a single pathology or a mixed dementia with AD. While the prevalence of type 2 diabetes in individuals with dementia can be as high as 39% and diabetes increases the risk of cerebrovascular disease and stroke, VCID remains to be one of the less understood and less studied complications of diabetes. We have identified cerebrovascular dysfunction and compromised endothelial integrity leading to decreased cerebral blood flow and iron deposition into the brain, respectively, as targets for intervention for the prevention of VCID in diabetes. This review will focus on targeted therapies that improve endothelial function or remove iron without systemic effects, such as agents delivered intranasally, that may result in actionable and disease-modifying novel treatments in the high-risk diabetic population.

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Section: Therapeutic Targets Insulinmentioning

confidence: 99%

Section: Therapeutic Targetsmentioning

confidence: 99%

Novel Targets and Interventions for Cognitive Complications of Diabetes

2022

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“…So, restoring insulin signaling might be advantageous to patients with AD. Amazingly, intranasal insulin administration, improves memory in healthy adults without affecting circulating levels of insulin and/or glucose[ 59 - 61 ]. In addition, intranasal insulin improves cognitive performance in patients with early AD[ 59 ].…”

Section: Glp1 and Dipeptidyl Peptidase-iv-inhibition Exhibits Neuroprotective Effects In Admentioning

confidence: 99%

“…Amazingly, intranasal insulin administration, improves memory in healthy adults without affecting circulating levels of insulin and/or glucose[ 59 - 61 ]. In addition, intranasal insulin improves cognitive performance in patients with early AD[ 59 ]. It is possible that therapeutic options for AD arise from this mechanism improving for neural insulin-resistance by the DPP4 inhibitors.…”

Section: Glp1 and Dipeptidyl Peptidase-iv-inhibition Exhibits Neuroprotective Effects In Admentioning

confidence: 99%

Neuroprotection by dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide-1 analogs via the modulation of AKT-signaling pathway in Alzheimer’s disease

Ikeda¹,

Nagase²,

Tsuji³

et al. 2021

WJBC

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Alzheimer’s disease (AD) is the most common reason for progressive dementia in the elderly. It has been shown that disorders of the mammalian/mechanistic target of rapamycin (mTOR) signaling pathways are related to the AD. On the other hand, diabetes mellitus (DM) is a risk factor for the cognitive dysfunction. The pathogenesis of the neuronal impairment caused by diabetic hyperglycemia is intricate, which contains neuro-inflammation and/or neurodegeneration and dementia. Glucagon-like peptide-1 (GLP1) is interesting as a possible link between metabolism and brain impairment. Modulation of GLP1 activity can influence amyloid-beta peptide aggregation via the phosphoinositide-3 kinase/AKT/mTOR signaling pathway in AD. The GLP1 receptor agonists have been shown to have favorable actions on the brain such as the improvement of neurological deficit. They might also exert a beneficial effect with refining learning and memory on the cognitive impairment induced by diabetes. Recent experimental and clinical evidence indicates that dipeptidyl-peptidase-4 (DPP4) inhibitors, being currently used for DM therapy, may also be effective for AD treatment. The DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models. Although further studies for mTOR, GLP1, and DPP4 signaling pathways in humans would be intensively required, they seem to be a promising approach for innovative AD-treatments. We would like to review the characteristics of AD pathogenesis, the key roles of mTOR in AD and the preventive and/ or therapeutic suggestions of directing the mTOR signaling pathway.

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“…Insulin is currently one of the most promising neuroprotective agents that are widely used in clinical trials. In pathological conditions such as type 2 diabetes mellitus, metabolic syndrome, Alzheimer’s and Parkinson’s diseases, the insulin level is increased markedly in blood, while in the brain, on the contrary, it is markedly diminished, which leads to disruption of insulin signaling in the hypothalamus and other regions of the brain [ 4 , 5 , 6 , 7 ]. Decreased levels of insulin in the brain and central insulin resistance lead to impaired metabolism and functional activity of neurons, as well as to the changes in hypothalamic regulation of carbohydrate and lipid metabolism, food intake and endocrine functions [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Insulin and α-Tocopherol Enhance the Protective Effect of Each Other on Brain Cortical Neurons under Oxidative Stress Conditions and in Rat Two-Vessel Forebrain Ischemia/Reperfusion Injury

Захарова

Bayunova

Zorina

et al. 2021

IJMS

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Clinical trials show that insulin administered intranasally is a promising drug to treat neurodegenerative diseases, but at high doses its use may result in cerebral insulin resistance. Identifying compounds which could enhance the protective effects of insulin, may be helpful to reduce its effective dose. Our aim was thus to study the efficiency of combined use of insulin and α-tocopherol (α-T) to increase the viability of cultured cortical neurons under oxidative stress conditions and to normalize the metabolic disturbances caused by free radical reaction activation in brain cortex of rats with two-vessel forebrain ischemia/reperfusion injury. Immunoblotting, flow cytometry, colorimetric, and fluorometric techniques were used. α-T enhanced the protective and antioxidative effects of insulin on neurons in oxidative stress, their effects were additive. At the late stages of oxidative stress, the combined action of insulin and α-T increased Akt-kinase activity, inactivated GSK-3beta and normalized ERK1/2 activity in cortical neurons, it was more effective than either drug action. In the brain cortex, ischemia/reperfusion increased the lipid peroxidation product content and caused Na+,K+-ATPase oxidative inactivation. Co-administration of insulin (intranasally, 0.25 IU/rat) and α-T (orally, 50 mg/kg) led to a more pronounced normalization of the levels of Schiff bases, conjugated dienes and trienes and Na+,K+-ATPase activity than administration of each drug alone. Thus, α-T enhances the protective effects of insulin on cultured cortical neurons in oxidative stress and in the brain cortex of rats with cerebral ischemia/reperfusion injury.

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Intranasal insulin and orexins to treat age-related cognitive decline

Cited by 21 publications

References 279 publications

Novel Targets and Interventions for Cognitive Complications of Diabetes

Novel Targets and Interventions for Cognitive Complications of Diabetes

Neuroprotection by dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide-1 analogs via the modulation of AKT-signaling pathway in Alzheimer’s disease

Insulin and α-Tocopherol Enhance the Protective Effect of Each Other on Brain Cortical Neurons under Oxidative Stress Conditions and in Rat Two-Vessel Forebrain Ischemia/Reperfusion Injury

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