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

Abstract

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.

Association of Cognitive Deficit with Glutamate and Insulin Signaling in a Rat Model of Parkinson's Disease

“…Summarizing the results, we can assume that disturbed dopamine signaling may be, to a lesser extent, transduced to insulin signaling and its downstream targets, as a secondary, collateral damage [50] like the one seen in HPT, but it probably depends on the 6-OHDA dose and the location of administration. In addition, intranasal insulin improves mitochondrial function, alleviates motor deficits and protects against substantia nigra dopaminergic neuronal loss in 6-OHDA rat model [64,65], suggesting neuroprotective insulin action.…”

Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium

“…The targets of action of insulin and IGF-1 in the CNS largely coincide, which is due to both the similar architecture of their signaling cascades and the ability of insulin and IGF-1 to activate the same receptors, including hybrid di/oligomeric forms of INSR/IGF1R [ 95 ]. In addition, both hormones have a similar pattern of regulatory effects on neurons and glial cells, exerting antiapoptotic and anti-inflammatory effects, as demonstrated for insulin in the use of INI for the treatment of neurodegenerative diseases, including AD [ 27 , 200 , 201 ]. All this allowed the group of Vera Novak to put forward a hypothesis about the prospects of using INI to correct cerebral ischemia [ 186 ].…”

The mitochondrial permeability transition pore: an evolving concept critical for cell life and death

“…The mPTP is a recognized mediator of neuronal death in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) (Sun et al, 2019), Parkinson's disease (Iravanpour et al, 2021), hypoxic-ischemic encephalopathy (Chen et al, 2021), and Alzheimer's disease (Du et al, 2008) in different animal models. Interestingly, increased activation of the mPTP in Alzheimer's disease was recorded even in non-neuronal tissues such as skin fibroblasts from patients (Perez et al, 2018).…”