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Saint Paul, MN, United States

Benedict C.,Uppsala University | Benedict C.,University of Lubeck | Frey W.H.,Alzheimers Research Center at Regions Hospital | Schioth H.B.,Uppsala University | And 3 more authors.
Experimental Gerontology | Year: 2011

The brain is a major target of circulating insulin. Enhancing central nervous insulin action has been shown to improve memory functions in animals as well as in humans, benefitting in particular hippocampus-dependent (declarative) memory. As Alzheimer's disease (AD) is associated with reduced central nervous insulin signaling and attenuated permeation of blood-borne insulin across the blood-brain-barrier, the cognitive decline in AD patients may at least in part be derived from impaired brain insulin signaling. Thus, therapeutic strategies to overcome central nervous system insulin deficiency and resistance might be an attractive option in the treatment of cognitive impairments like AD. Insulin can be effectively delivered directly to the brain via the intranasal route that enables the hormone to bypass the blood-brain barrier and modulate central nervous functions. This review summarizes a series of studies demonstrating beneficial effects of intranasal insulin on memory functions both in healthy humans and in patients with cognitive impairments such as AD. These experiments in humans consistently indicate that enhancing brain insulin signaling by intranasal administration of the hormone improves hippocampus-dependent memory in the absence of adverse side effects. Considering that insulin also acts as a neuroprotective signal, up-regulating brain insulin levels by intranasal insulin administration appears to be a promising approach in the treatment and prevention of central nervous system insulin deficiency and resistance as found in AD. © 2010 Elsevier Inc.

Toth C.C.,University of Calgary | Jedrzejewski N.M.,University of Calgary | Ellis C.L.,University of Calgary | Frey II W.H.,Alzheimers Research Center at Regions Hospital
Molecular Pain | Year: 2010

Background: Despite the frequency of diabetes mellitus and its relationship to diabetic peripheral neuropathy (DPN) and neuropathic pain (NeP), our understanding of underlying mechanisms leading to chronic pain in diabetes remains poor. Recent evidence has demonstated a prominent role of microglial cells in neuropathic pain states. One potential therapeutic option gaining clinical acceptance is the cannabinoids, for which cannabinoid receptors (CB) are expressed on neurons and microglia. We studied the accumulation and activation of spinal and thalamic microglia in streptozotocin (STZ)-diabetic CD1 mice and the impact of cannabinoid receptor agonism/antagonism during the development of a chronic NeP state. We provided either intranasal or intraperitoneal cannabinoid agonists/antagonists at multiple doses both at the initiation of diabetes as well as after establishment of diabetes and its related NeP state.Results: Tactile allodynia and thermal hypersensitivity were observed over 8 months in diabetic mice without intervention. Microglial density increases were seen in the dorsal spinal cord and in thalamic nuclei and were accompanied by elevation of phosphorylated p38 MAPK, a marker of microglial activation. When initiated coincidentally with diabetes, moderate-high doses of intranasal cannabidiol (cannaboid receptor 2 agonist) and intraperitoneal cannabidiol attenuated the development of an NeP state, even after their discontinuation and without modification of the diabetic state. Cannabidiol was also associated with restriction in elevation of microglial density in the dorsal spinal cord and elevation in phosphorylated p38 MAPK. When initiated in an established DPN NeP state, both CB1 and CB2 agonists demonstrated an antinociceptive effect until their discontinuation. There were no pronociceptive effects demonstated for either CB1 or CB2 antagonists.Conclusions: The prevention of microglial accumulation and activation in the dorsal spinal cord was associated with limited development of a neuropathic pain state. Cannabinoids demonstrated antinociceptive effects in this mouse model of DPN. These results suggest that such interventions may also benefit humans with DPN, and their early introduction may also modify the development of the NeP state. © 2010 Toth et al; licensee BioMed Central Ltd.

Whitebird R.R.,HealthPartners Research Foundation | Kreitzer M.J.,University of Minnesota | Lewis B.A.,University of Minnesota | Hanson L.R.,Alzheimers Research Center at Regions Hospital | And 3 more authors.
Contemporary Clinical Trials | Year: 2011

Caregivers for a family member with dementia experience chronic long-term stress that may benefit from new complementary therapies such as mindfulness-based stress reduction. Little is known however, about the challenges of recruiting and retaining family caregivers to research on mind-body based complementary therapies. Our pilot study is the first of its kind to successfully recruit caregivers for a family member with dementia to a randomized controlled pilot study of mindfulness-based stress reduction. The study used an array of recruitment strategies and techniques that were tailored to fit the unique features of our recruitment sources and employed retention strategies that placed high value on establishing early and ongoing communication with potential participants. Innovative recruitment methods including conducting outreach to health plan members and generating press coverage were combined with standard methods of community outreach and paid advertising. We were successful in exceeding our recruitment goal and retained 92% of the study participants at post-intervention (2 months) and 90% at 6 months. Recruitment and retention for family caregiver interventions employing mind-body based complementary therapies can be successful despite many challenges. Barriers include cultural perceptions about the use and benefit of complementary therapies, cultural differences with how the role of family caregiver is perceived, the use of group-based designs requiring significant time commitment by participants, and travel and respite care needs for busy family caregivers. © 2011 Elsevier Inc.

Francis G.J.,Hotchkiss Brain Institute | Martinez J.A.,Hotchkiss Brain Institute | Liu W.Q.,Hotchkiss Brain Institute | Zochodne D.W.,Hotchkiss Brain Institute | And 6 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2011

Retraction of distal sensory axons is a prominent feature in diabetic peripheral neuropathy (DPN), a process amenable to insulin therapy. Nevertheless, diabetic patients and long-term diabetic mice develop motor deficits after longer durations of DPN, a process that may be related to insulin deficiency. To compare the efficacy of intranasal delivery of insulin (IN-I) and subcutaneous insulin (Subc-I) in preventing motor deficits in a long-term mouse model of DPN, IN-I or Subc-I, 0.87 IU daily or placebo was delivered in separate cohorts of diabetic and nondiabetic CD1 mice for 8 months. Radiolabeled detection was used to assess insulin delivery and biodistribution. Biweekly behavioral tests and monthly electrophysiological and multipoint quantitative studies assessed motor function deficits. Morphometric analysis of spinal cord, peripheral nerve, muscle innervation, and specific molecular markers were evaluated at and before the end point. Despite progressive distal axonal terminal loss, numbers and caliber ofmotor neurons were preserved. There were no differences in glycemia between IN-I and Subc-I-treated mice. Intranasal delivery of insulin and, to a lesser extent, Subc-I, protected against electrophysiological decline, loss of neuromuscular junctions, and loss of motor behavioral skills. Intranasal delivery of insulin was associated with greater preservation of the phosphatidylinositol 3-kinase signaling pathway involving Akt, cyclic AMP response element binding protein,and glycogen synthase kinase 3β but did not alter extracellular signal-regulated kinase, mitogen-activated protein kinase/extracellular signal-regulated kinase, or c-Jun amino-terminal kinase. Thus, direct delivery of insulin to the nervous system might prevent motor deficit in human type 1 diabetes by preservation of the phosphatidylinositol 3-kinase-Akt pathway rather than only affecting glycemic levels; the effects of insulin on other signaling pathways may, however, play additional roles. © 2011 by the American Association of Neuropathologists, Inc.

Wolf D.A.,University of Minnesota | Hanson L.R.,Alzheimers Research Center at Regions Hospital | Aronovich E.L.,University of Minnesota | Nan Z.,University of Minnesota | And 3 more authors.
Molecular Genetics and Metabolism | Year: 2012

Here we provide the first evidence that therapeutic levels of a lysosomal enzyme can bypass the blood-brain barrier following intranasal administration α-l-iduronidase (IDUA) activity was detected throughout the brains of IDUA-deficient mice following a single intranasal treatment with concentrated Aldurazyme® (laronidase) and was also detected after intranasal treatment with an adeno-associated virus (AAV) vector expressing human IDUA. These results suggest that intranasal routes of delivery may be efficacious in the treatment of lysosomal storage disorders. © 2012.

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