Intranasal delivery of low-dose insulin ameliorates motor dysfunction and dopaminergic cell death in a 6-OHDA rat model of Parkinson’s Disease

Fine, Jared M.; Stroebel, Benjamin M.; Faltesek, Katherine A.; Terai, Kaoru; Haase, L.R.; Knutzen, Kristin E.; Kosyakovsky, Jacob; Bowe, Tate J.; Fuller, Austin K.; Frey, William H.; Hanson, Leah R.

doi:10.1016/j.neulet.2019.134567

Cited by 35 publications

(22 citation statements)

References 28 publications

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“…In current study, we found that IN insulin could rescue dopaminergic neurons against cell death induced by 6‐OHDA, and ameliorate motor deficits in a rat model of PD, which is consistent with previous studies 9,11 …”

Section: Discussionsupporting

confidence: 92%

“…Regarding the neuroprotective effects of insulin in the brain, 7 and the probable causative role of insulin resistance in PD pathogenesis, 8 emerging studies continue to demonstrate the beneficial effects of intranasal (IN) insulin in both animal models of PD and humans in clinical trials 9–11 . The insulin receptors are widely found in basal ganglia and SN and insulin is described as a critical regulator of energy balance, neuronal survival, and growth, neurotransmission, and maintenance of synapses in brain 12 .…”

Section: Introductionmentioning

confidence: 99%

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Intranasal insulin improves mitochondrial function and attenuates motor deficits in a rat 6‐OHDA model of Parkinson's disease

et al. 2021

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Aims Experimental and clinical evidences demonstrate that common dysregulated pathways are involved in Parkinson’s disease (PD) and type 2 diabetes. Recently, insulin treatment through intranasal (IN) approach has gained attention in PD, although the underlying mechanism of its potential therapeutic effects is still unclear. In this study, we investigated the effects of insulin treatment in a rat model of PD with emphasis on mitochondrial function indices in striatum. Methods Rats were treated with a daily low dose (4IU/day) of IN insulin, starting 72 h after 6‐OHDA‐induced lesion and continued for 14 days. Motor performance, dopaminergic cell survival, mitochondrial dehydrogenases activity, mitochondrial swelling, mitochondria permeability transition pore (mPTP), mitochondrial membrane potential (Δψm), reactive oxygen species (ROS) formation, and glutathione (GSH) content in mitochondria, mitochondrial adenosine triphosphate (ATP), and the gene expression of PGC‐1α, TFAM, Drp‐1, GFAP, and Iba‐1 were assessed. Results Intranasal insulin significantly reduces 6‐OHDA‐induced motor dysfunction and dopaminergic cell death. In parallel, it improves mitochondrial function indices and modulates mitochondria biogenesis and fission as well as activation of astrocytes and microglia. Conclusion Considering the prominent role of mitochondrial dysfunction in PD pathology, IN insulin as a disease‐modifying therapy for PD should be considered for extensive research.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Intranasal insulin improves mitochondrial function and attenuates motor deficits in a rat 6‐OHDA model of Parkinson's disease

et al. 2021

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“…In the six OHDA rat model of PD, both a daily high dose (12IU) for 2 weeks and a daily low dose (3IU) for 4 weeks of intranasal insulin alleviated motor deficits observed in the model in overall locomotor activity and in a variety of motor behavioral tests (Pang et al, 2016;Fine et al, 2020). Pang et al (2016) demonstrated that insulin delivered intranasally did not affect body weight or blood glucose levels, but was detectable in the CSF within minutes of administration.…”

Section: Insulin Therapymentioning

confidence: 99%

“…Improved cognition and working memory Improved delayed verbal and story recall task performances Chen et al, 2014;Salameh et al, 2015;Mao et al, 2016;Guo et al, 2017Hanson and Frey, 2008Hanson and Frey, 2008Reger et al, 2008;Claxton et al, 2015Reger et al, 2006Craft et al, 2012Craft et al, , 2017 Varied efficacy dependent on genotype Craft et al, 2000Craft et al, , 2003 Parkinson's disease Pang et al, 2016;Fine et al, 2020Pang et al, 2016Novak et al, 2019Novak et al, 2019Novak et al, 2019 N/A of a diabetes model via streptozotocin in rats, can significantly worsen the outcome of a SCI (Tariq et al, 1998). Motor function after a moderate compression thoracic injury was markedly worsened from 1 to 10 days after injury in streptozotocin treated rats.…”

Section: No Hypoglycemiamentioning

confidence: 99%

Role of Insulin in Neurotrauma and Neurodegeneration: A Review

et al. 2020

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Insulin is a hormone typically associated with pancreatic release and blood sugar regulation. The brain was long thought to be "insulin-independent," but research has shown that insulin receptors (IR) are expressed on neurons, microglia and astrocytes, among other cells. The effects of insulin on cells within the central nervous system are varied, and can include both metabolic and non-metabolic functions. Emerging data suggests that insulin can improve neuronal survival or recovery after trauma or during neurodegenerative diseases. Further, data suggests a strong antiinflammatory component of insulin, which may also play a role in both neurotrauma and neurodegeneration. As a result, administration of exogenous insulin, either via systemic or intranasal routes, is an increasing area of focus in research in neurotrauma and neurodegenerative disorders. This review will explore the literature to date on the role of insulin in neurotrauma and neurodegeneration, with a focus on traumatic brain injury (TBI), spinal cord injury (SCI), Alzheimer's disease (AD) and Parkinson's disease (PD).

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“…In animal models of neurodegenerative diseases, exogenous insulin, administered intranasally or topically, demonstrates neuroprotective effects such as promoting neuronal survival, enhancing mitochondrial function, and reducing neuro-inflammation. In models of AD and PD, these effects ameliorate cognitive and motor impairment [ 124 , 125 , 126 , 127 , 128 , 129 , 130 ]. Table 1 demonstrates the neuroprotective effects of exogenous insulin use in examples of experimental models of AD, PD, glaucoma, and HIV-associated neurocognitive disorder (HAND).…”

Section: Targeting Insulin Resistance Therapeutically In Neurodegenerationmentioning

confidence: 99%

Insulin Signaling as a Therapeutic Target in Glaucomatous Neurodegeneration

Wareham

Risner

Calkins

2021

IJMS

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Glaucoma is a multifactorial disease that is conventionally managed with treatments to lower intraocular pressure (IOP). Despite these efforts, many patients continue to lose their vision. The degeneration of retinal ganglion cells (RGCs) and their axons in the optic tract that characterizes glaucoma is similar to neurodegeneration in other age-related disorders of the central nervous system (CNS). Identifying the different molecular signaling pathways that contribute to early neuronal dysfunction can be utilized for neuroprotective strategies that prevent degeneration. The discovery of insulin and its receptor in the CNS and retina led to exploration of the role of insulin signaling in the CNS. Historically, insulin was considered a peripherally secreted hormone that regulated glucose homeostasis, with no obvious roles in the CNS. However, a growing number of pre-clinical and clinical studies have demonstrated the potential of modulating insulin signaling in the treatment of neurodegenerative diseases. This review will highlight the role that insulin signaling plays in RGC neurodegeneration. We will focus on how this pathway can be therapeutically targeted to promote RGC axon survival and preserve vision.

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Intranasal delivery of low-dose insulin ameliorates motor dysfunction and dopaminergic cell death in a 6-OHDA rat model of Parkinson’s Disease

Cited by 35 publications

References 28 publications

Intranasal insulin improves mitochondrial function and attenuates motor deficits in a rat 6‐OHDA model of Parkinson's disease

Intranasal insulin improves mitochondrial function and attenuates motor deficits in a rat 6‐OHDA model of Parkinson's disease

Role of Insulin in Neurotrauma and Neurodegeneration: A Review

Insulin Signaling as a Therapeutic Target in Glaucomatous Neurodegeneration

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