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Distribution of insulin in trigeminal nerve and brain after intranasal administration.

ABSTRACT: In the brain, insulin acts as a growth factor, regulates energy homeostasis, and is involved in learning and memory acquisition. Many central nervous system (CNS) diseases are characterized by deficits in insulin signaling. Pre-clinical studies have shown that intranasal insulin is neuroprotective in models of Alzheimer's disease, Parkinson's disease, and traumatic brain injury. Clinical trials have also shown that intranasal insulin elicits beneficial cognitive effects in patients with Alzheimer's disease. It is known that insulin can be detected in the CNS within minutes following intranasal administration. Despite these advances, the anatomical pathways that insulin utilizes to reach the CNS and the cellular CNS targets after intranasal administration are not fully understood. Here, we intranasally administered fluorescently labeled insulin and imaged its localization within the brain and trigeminal nerves. Our data indicates that intranasal insulin can reach cellular CNS targets along extracellular components of the trigeminal nerve. Upon CNS entry, we found insulin significantly increased levels of an activated form of the insulin receptor. These findings suggest that the intranasal route of administration is able to effectively deliver insulin to CNS targets in a biologically active form.

SUBMITTER: Lochhead JJ

PROVIDER: S-EPMC6385374 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Distribution of insulin in trigeminal nerve and brain after intranasal administration.

Lochhead Jeffrey J JJ Kellohen Kathryn L KL Ronaldson Patrick T PT Davis Thomas P TP

Scientific reports 20190222 1

In the brain, insulin acts as a growth factor, regulates energy homeostasis, and is involved in learning and memory acquisition. Many central nervous system (CNS) diseases are characterized by deficits in insulin signaling. Pre-clinical studies have shown that intranasal insulin is neuroprotective in models of Alzheimer's disease, Parkinson's disease, and traumatic brain injury. Clinical trials have also shown that intranasal insulin elicits beneficial cognitive effects in patients with Alzheime ...[more]

PMID: 30796294

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Project description:We previously reported that intranasal insulin protects substantia nigra dopaminergic neurons against 6-hydroxydopamine neurotoxicity in rats. This study aimed to assess insulin pharmacokinetics in the rat brain following intranasal application. Recombinant human insulin (rh-Ins) or phosphate buffer solution was administered to both nostrils of rats. Animals were sacrificed at 15 minutes, 1, 2, and 6 hours to determine insulin levels in different brain regions by an ultrasensitive, human-specific enzyme-linked immunosorbent assay kit. For fluorescence tracing study, rats were administered with intranasal florescence-tagged insulin (Alex546-Ins), and brains were fixed at 10 and 30 minutes to prepare sagittal sections. rh-Ins was detected in all brain regions examined except the cerebral cortex. The highest levels were detected in the brainstem, followed by the cerebellum, substantia nigra/ventral tegmental area, olfactory bulb, striatum, hippocampus, and thalamus/hypothalamus. Insulin levels reached a peak at 15 minutes and then declined gradually overtime, but remained significantly higher than baseline levels at 6 hours in most regions. Consistently, widespread Alex546-Ins-binding cells were detected in the brain at 10 and 30 minutes, with the olfactory bulb and brainstem showing the highest while the cerebral cortex showing lowest fluorescence signals. Double-immunostaining showed that Alex546-Ins-bindings were primarily co-localized with neuronal nuclei-positive neurons. In the subtantia nigra, phospho-Akt was found to be activated in a subset of Alex546-Ins and tyrosine hydroxylase double-labeled cells, suggesting activation of the Akt/PI3K pathway in these dopaminergic neurons. Data from this study suggest that intranasal insulin could effectively reach deep brain structures including the nigrostriatal pathways, where it binds to dopaminergic neurons and activates intracellular cell survival signaling. This study was approved by the Institutional Animal Care Committee at the University of Mississippi Medical Center (protocol 1333A) on June 29, 2015.

Project description:The pathophysiology of migraine remains to be elucidated. We have recently shown that interictal migraineurs exhibit reduced fractional anisotropy (FA) in the root entry zone of the trigeminal nerve when compared to controls, but it is not known if this altered nerve anatomy is associated with changes within the brainstem or higher cortical brain regions. Diffusion tensor imaging of the brain was used to calculate regional measures of structure, including mean diffusivity (MD), axial diffusivity (AX) and radial diffusivity (RD) in addition to voxel-based morphometry of T1-weighted anatomical images. Linear relationships between trigeminal nerve anatomy (FA) and MD throughout the brainstem and/or higher cortical regions were determined in both controls (n = 31, brainstem; n = 38, wholebrain) and interictal migraineurs (n = 32, brainstem; n = 38, wholebrain). Additionally, within the same brain areas, relationships of AX and RD with nerve FA were determined. We found that in both interictal migraine and control participants, decreasing trigeminal nerve FA was associated with significantly increased MD in brainstem regions including the spinal trigeminal nucleus and midbrain periaqueductal gray matter (PAG), and in higher brain regions such as the hypothalamus, insula, posterior cingulate, primary somatosensory and primary visual (V1) cortices. Whereas, both control and migraineur groups individually displayed significant inverse correlations between nerve FA and MD, in migraineurs this pattern was disrupted in the areas of the PAG and V1, with only the control group displaying a significant linear relationship (PAG controls r = -0.58, p = 0.003; migraineurs r = -0.25, p = 0.17 and V1 controls r = -0.52, p = 0.002; migraineurs r = -0.10, p = 0.55). Contrastingly, we found no gray matter volume changes in brainstem or wholebrain areas. These data show that overall, trigeminal nerve anatomy is significantly related to regional brain structure in both controls and migraineurs. Importantly, the PAG showed a disruption of this relationship in migraineurs suggesting that the anatomy and possibly the function of the PAG is uniquely altered in episodic migraine, which may contribute to altered orofacial pain processing in migraine.

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Distribution of insulin in trigeminal nerve and brain after intranasal administration.

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Distribution of insulin in trigeminal nerve and brain after intranasal administration.

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