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Saint Paul, MN, United States

Freiherr J.,RWTH Aachen | Hallschmid M.,University of Tubingen | Hallschmid M.,Helmholtz Center Munich | Frey II W.H.,Alzheimers Research Center | And 6 more authors.
CNS Drugs | Year: 2013

Research in animals and humans has associated Alzheimer's disease (AD) with decreased cerebrospinal fluid levels of insulin in combination with decreased insulin sensitivity (insulin resistance) in the brain. This phenomenon is accompanied by attenuated receptor expression of insulin and insulin-like growth factor, enhanced serine phosphorylation of insulin receptor substrate-1, and impaired transport of insulin across the blood-brain barrier. Moreover, clinical trials have demonstrated that intranasal insulin improves both memory performance and metabolic integrity of the brain in patients suffering from AD or its prodrome, mild cognitive impairment. These results, in conjunction with the finding that insulin mitigates hippocampal synapse vulnerability to beta amyloid, a peptide thought to be causative in the development of AD, provide a strong rationale for hypothesizing that pharmacological strategies bolstering brain insulin signaling, such as intranasal administration of insulin, could have significant potential in the treatment and prevention of AD. With this view in mind, the review at hand will present molecular mechanisms potentially underlying the memory-enhancing and neuroprotective effects of intranasal insulin. Then, we will discuss the results of intranasal insulin studies that have demonstrated that enhancing brain insulin signaling improves memory and learning processes in both cognitively healthy and impaired humans. Finally, we will provide an overview of neuroimaging studies indicating that disturbances in insulin metabolism - such as insulin resistance in obesity, type 2 diabetes and AD - and altered brain responses to insulin are linked to decreased cerebral volume and especially to hippocampal atrophy. © 2013 The Author(s). Source


Fine J.M.,Alzheimers Research Center | Baillargeon A.M.,Alzheimers Research Center | Renner D.B.,Alzheimers Research Center | Hoerster N.S.,Alzheimers Research Center | And 9 more authors.
Experimental Brain Research | Year: 2012

Deferoxamine (DFO), a metal chelator, has been previously reported to slow the loss of spatial memory in a mouse model of amyloid accumulation when delivered intranasally (IN). In this study, we determined whether IN DFO also has beneficial effects in the P301L mouse, which accumulates hyperphosphorylated tau. Mice were intranasally treated three times per week with either 10 % DFO (2.4 mg) or saline for 5 months, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with Western blot and ELISA. Wild-type (WT) mice statistically outperformed transgenic (TG) saline mice in the radial arm water maze, while performance of TG-DFO mice was not different than WT mice, suggesting improved performance in the radial arm water maze. Other behavioral changes were not evident. Beneficial changes in brain biochemistry were evident in DFO-treated mice for several proteins. The TG mice had significantly less pGSK3β and HIF-1α, with more interleukin-1β and total protein oxidation than wild-type controls, and for each protein, DFO treatment significantly reduced these differences. There was not a significant decrease in phosphorylated tau in brain tissue of DFOtreated mice at the sites we measured. These data suggest that IN DFO is a potential treatment not only for Alzheimer's disease, but also for other neurodegenerative diseases and psychiatric disorders in which GSK3β and HIF- 1α play a prominent role. © Springer-Verlag 2012. Source


Martinez J.A.,University of Calgary | Kasamatsu M.,University of Calgary | Rosales-Hernandez A.,University of Calgary | Hanson L.R.,Alzheimers Research Center | And 3 more authors.
Molecular Pain | Year: 2012

Background: Although pregabalin therapy is beneficial for neuropathic pain (NeP) by targeting the CaVα 2δ-1 subunit, its site of action is uncertain. Direct targeting of the central nervous system may be beneficial for the avoidance of systemic side effects.Results: We used intranasal, intrathecal, and near-nerve chamber forms of delivery of varying concentrations of pregabalin or saline delivered over 14 days in rat models of experimental diabetic peripheral neuropathy and spinal nerve ligation. As well, radiolabelled pregabalin was administered to determine localization with different deliveries. We evaluated tactile allodynia and thermal hyperalgesia at multiple time points, and then analyzed harvested nervous system tissues for molecular and immunohistochemical changes in CaVα 2δ-1 protein expression. Both intrathecal and intranasal pregabalin administration at high concentrations relieved NeP behaviors, while near-nerve pregabalin delivery had no effect. NeP was associated with upregulation of CACNA2D1 mRNA and CaVα 2δ-1 protein within peripheral nerve, dorsal root ganglia (DRG), and dorsal spinal cord, but not brain. Pregabalin's effect was limited to suppression of CaVα 2δ-1 protein (but not CACNA2D1 mRNA) expression at the spinal dorsal horn in neuropathic pain states. Dorsal root ligation prevented CaVα 2δ-1 protein trafficking anterograde from the dorsal root ganglia to the dorsal horn after neuropathic pain initiation.Conclusions: Either intranasal or intrathecal pregabalin relieves neuropathic pain behaviours, perhaps due to pregabalin's effect upon anterograde CaVα 2δ-1 protein trafficking from the DRG to the dorsal horn. Intranasal delivery of agents such as pregabalin may be an attractive alternative to systemic therapy for management of neuropathic pain states. © 2012 Martinez et al; licensee BioMed Central Ltd. Source


Danielyan L.,University of Tubingen | Schafer R.,University of Tubingen | Schafer R.,Harvard Stem Cell Institute | Von Ameln-Mayerhofer A.,University of Tubingen | And 19 more authors.
Rejuvenation Research | Year: 2011

Safe and effective cell delivery remains one of the main challenges in cell-based therapy of neurodegenerative disorders. Graft survival, sufficient enrichment of therapeutic cells in the brain, and avoidance of their distribution throughout the peripheral organs are greatly influenced by the method of delivery. Here we demonstrate for the first time noninvasive intranasal (IN) delivery of mesenchymal stem cells (MSCs) to the brains of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. IN application (INA) of MSCs resulted in the appearance of cells in the olfactory bulb, cortex, hippocampus, striatum, cerebellum, brainstem, and spinal cord. Out of 1×106 MSCs applied intranasally, 24% survived for at least 4.5 months in the brains of 6-OHDA rats as assessed by quantification of enhanced green fluorescent protein (EGFP) DNA. Quantification of proliferating cell nuclear antigen-positive EGFP-MSCs showed that 3% of applied MSCs were proliferative 4.5 months after application. INA of MSCs increased the tyrosine hydroxylase level in the lesioned ipsilateral striatum and substantia nigra, and completely eliminated the 6-OHDA-induced increase in terminal deoxynucleotidyl transferase (TdT)-mediated 2′-deoxyuridine, 5′-triphosphate (dUTP)-biotin nick end labeling (TUNEL) staining of these areas. INA of EGFP-labeled MSCs prevented any decrease in the dopamine level in the lesioned hemisphere, whereas the lesioned side of the control animals revealed significantly lower levels of dopamine 4.5 months after 6-OHDA treatment. Behavioral analyses revealed significant and substantial improvement of motor function of the Parkinsonian forepaw to up to 68% of the normal value 40-110 days after INA of 1×106 cells. MSC-INA decreased the concentrations of inflammatory cytokines-interleukin-1β (IL-1β), IL-2, -6, -12, tumor necrosis factor (TNF), interferon-γ (IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF)-in the lesioned side to their levels in the intact hemisphere. IN administration provides a highly promising noninvasive alternative to the traumatic surgical procedure of transplantation and allows targeted delivery of cells to the brain with the option of chronic application. © 2011 Mary Ann Liebert, Inc. Source


Whitebird R.R.,HealthPartners Institute for Education and Research | Kreitzer M.,University of Minnesota | Lauren Crain A.,HealthPartners Institute for Education and Research | Lewis B.A.,University of Minnesota | And 2 more authors.
Gerontologist | Year: 2013

Purpose: Caring for a family member with dementia is associated with chronic stress, which can have significant deleterious effects on caregivers. The purpose of the Balance Study was to compare a mindfulness-based stress reduction (MBSR) intervention to a community caregiver education and support (CCES) intervention for family caregivers of people with dementia. Design and Methods: We randomly assigned 78 family caregivers to an MBSR or a CCES intervention, matched for time and attention. Study participants attended 8 weekly intervention sessions and participated in home-based practice. Surveys were completed at baseline, postintervention, and at 6 months. Participants were 32- to 82-year-old predominately non-Hispanic White women caring for a parent with dementia. Results: MBSR was more effective at improving overall mental health, reducing stress, and decreasing depression than CCES. Both interventions improved caregiver mental health and were similarly effective at improving anxiety, social support, and burden. Implications: MBSR could reduce stress and improve mental health in caregivers of family members with dementia residing in the community. © The Author 2013. Source

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