Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer's disease (AD) models. However, their beneficial effects on memory deficits, cholinergic ...activity, neurogenesis and Amyloid beta (Aβ) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also targeting and therapeutic efficacy of ARBs. Our previous findings on the beneficial effects of intranasally delivered losartan in the APP/PS1 model of AD prompted us to explore the influence of the delivery route by employing here the systemic administration of losartan. Consistent with our previous results with intranasal losartan, repeated intraperitoneal administration (10 mg/kg) resulted in a remarkable decrease in Aβ plaques and soluble Aβ42, as well as inflammatory cytokines (IL-2, IL-6 and TNFα). The Aβ reduction can be ascribed to its facilitated degradation by neprilysin and diminished generation by BACE1. Losartan increased neurogenesis in vivo and in vitro and improved migratory properties of astrocytes isolated from adult transgenic AD mice. In summary, this data together with our previous results suggest therapeutic features of losartan which are independent of delivery route. The improvement of cell motility of Aβ-affected astrocytes by losartan deserves further
investigation, which may lead to new strategies for AD treatment.
Background
Individuals with Down syndrome are likely to develop clinical and neuropathological brain changes resembling Alzheimer’s disease dementia by the ages of 35–40 years. Intranasal insulin is ...a potential treatment for neurodegenerative disease that has been shown to reduce amyloid plaque burden and improve verbal memory performance in normal as well as memory-impaired adults. Investigations have shown that rapid-acting insulins may result in superior cognitive benefits compared with regular insulin.
Objectives
The primary objective of this study was to measure the safety and feasibility of intranasal rapid-acting glulisine in subjects with Down syndrome. Secondarily, we estimated the effects of intranasal glulisine on cognition and memory in Down syndrome.
Methods
A single-center, single-dose, randomized, double-blind, placebo-controlled, cross-over pilot study was performed to test the safety of intranasal glulisine vs placebo in 12 subjects with Down syndrome aged ≥ 35 years. Intranasal administration utilized the Impel NeuroPharma I109 Precision Olfactory Delivery (POD
®
) device. The primary outcomes were the occurrence of any or related adverse and serious adverse events. Secondary post-treatment cognitive outcome measures included performance on the Fuld Object-Memory Evaluation and Rivermead Behavioral Memory Test.
Results
Intranasal glulisine was safe and well tolerated in the Down syndrome population. No adverse or serious adverse events were observed.
Conclusions
Further investigations are necessary to better evaluate the potential cognitive-enhancing role of intranasal insulin in the Down syndrome population.
ClinicalTrials.gov ID
NCT02432716.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The ability of a novel intranasally delivered amnion cell derived biologic to suppress inflammation, prevent neuronal damage and preserve neurologic function in the experimental autoimmune ...encephalomyelitis animal model of multiple sclerosis was assessed. Currently, there are no existing optic nerve treatment methods for disease or trauma that result in permanent vision loss. Demyelinating optic nerve inflammation, termed optic neuritis, induces permanent visual dysfunction due to retinal ganglion cell damage in multiple sclerosis and experimental autoimmune encephalomyelitis. ST266, the biological secretome of Amnion-derived Multipotent Progenitor cells, contains multiple anti-inflammatory cytokines and growth factors. Intranasally administered ST266 accumulated in rodent eyes and optic nerves, attenuated visual dysfunction, and prevented retinal ganglion cell loss in experimental optic neuritis, with reduced inflammation and demyelination. Additionally, ST266 reduced retinal ganglion cell death in vitro. Neuroprotective effects involved oxidative stress reduction, SIRT1-mediated mitochondrial function promotion, and pAKT signaling. Intranasal delivery of neuroprotective ST266 is a potential novel, noninvasive therapeutic modality for the eyes, optic nerves and brain. The unique combination of biologic molecules in ST266 provides an innovative approach with broad implications for suppressing inflammation in autoimmune diseases, and for preventing neuronal damage in acute neuronal injury and chronic neurodegenerative diseases such as multiple sclerosis.
The recent increase in opioid misuse and overdose among the Hispanic population signifies the need for an initiative to increase efforts in pain management in the Hispanic population. Yoga is an ...evidence-based therapeutic intervention that is effective for several pain-associated disorders. However, in the United States, it is primarily taught in English and not always accessible. This quality improvement (QI) project aimed to assess the outcome of implementing a yoga program on pain and quality of life in the Hispanic population.
Twenty Spanish-speaking community center members participated in a linguistically-tailored yoga program over the course of 10 weeks that included educational, demonstration, and practice videos. Outcome measures of the QI program included changes in pain interference, physical function, opioid medication use, overall impression of change in pain, satisfaction with the program, and likelihood of continuation of yoga practice.
Data collected from participants (n=16) after the 10-week period indicated that nearly 60% experienced an improvement in their overall impression of change in pain; their reported likelihood of continuation of yoga practice at home or at another location were 6.8 and 7.4, respectively, on a 10-point scale. While pain interference was unaffected, there was an improvement in markers of physical function, including a two-fold improvement in general activity without limitations. The mean average intensity of pain decreased by 33%.
Use of a linguistically-tailored yoga program improved self-reported overall pain, physical function, average intensity of pain, and initiated an interest in participants in utilizing yoga practice for self-management of pain. This QI project provides results that can be used for further implementation initiatives at other sites and consideration of use in diverse populations.
► Intranasal siRNA penetrates the olfactory epithelium and lamina propria. ► The olfactory nerve mediates intranasal delivery of siRNA to the olfactory bulb. ► Intranasal siRNA distributes in ...olfactory nerve, glomerular and mitral cell layers. ► Results support potential applications of intranasal siRNA for silencing in CNS.
Adopting RNAi technology for targeted manipulation of gene expression in the central nervous system (CNS) will require delivery of RNAi constructs to the CNS followed by cellular transfection and induction of the RNAi machinery. Significant strides have been made in enhancing RNAi transfection and tailoring knockdown toward specific gene targets, however, delivery of the RNAi constructs to the CNS remains a significant challenge. One possible solution for targeting siRNA to the CNS is intranasal administration, which noninvasively delivers a variety of compounds to the CNS. The current study examined delivery of fluorescently labeled siRNA from the nasal cavity to the olfactory bulbs via the olfactory nerve pathway. siRNA was observed along the length of the olfactory nerve bundles, from the olfactory mucosa of the nasal cavity to the anterior regions of the olfactory bulbs. In the olfactory mucosa, labeled siRNA was found within the olfactory epithelium, Bowman's glands, and associated with blood vessels and bundles of olfactory nerves. In the olfactory bulbs, siRNA was observed in the olfactory nerve, glomerular and mitral cell layers. These results demonstrate a role of the olfactory nerve pathway in targeting siRNA to the olfactory bulbs. Additional investigations will be required to assess the distribution of intranasal siRNA to additional regions of the brain and explore the capacity of the delivered siRNA to silence gene expression in the CNS.
The local renin-angiotensin system (RAS) in the brain is a multitasking system controlling a plethora of essential functions such as neurogenic hypertension, baroreflexes, and sympathetic activity. ...Aside from its vasoactive actions, brain angiotensin II (AT-II) has also been implicated in the pathogenesis of cognitive decline, and beneficial effects of angiotensin receptor blockers (ARBs) in Alzheimer (AD) and Parkinson diseases (PD) are suggested. However, the use of ARBs at antihypertensive dosages would lead to unwanted hypotensive reactions in AD patients. Here we treated the APP/PS1 transgenic mouse model of AD with the ARB losartan (10 mg/kg body weight) to determine whether blockade of the AT-II receptor subtype 1 (AT1-R) with intranasal losartan, using at a dosage far below its systemic antihypertensive dose, could maintain its neuroprotective effects independent of its systemic vasoactive action. Intranasal losartan treatment (10 mg/kg every other day for 2 months) of APP/PS1 mice decreased amyloid beta (Abeta) plaques 3.7-fold. Blood serum levels of interleukin-12 (IL-12)p40/p70, IL-1beta, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased in the vehicle-treated APP/PS1 mice. Intranasal losartan not only decreased IL-12p40/p70, IL-1beta, and GM-CSF, but also increased IL-10, which suppresses inflammation. Furthermore, losartan markedly increased tyrosine hydroxylase expression in the striatum and locus coeruleus. In conclusion, losartan exerts direct neuroprotective effects via its Abeta-reducing and antiinflammatory effects in the central nervous system (CNS). Therefore, intranasal losartan and potentially other ARBs, at concentrations below their threshold for altering systemic blood pressure, offer a new approach for the treatment of AD.
The intranasal route of drug administration is noninvasive, convenient, and rapidly targets therapeutics to the central nervous system (CNS) using olfactory and trigeminal neural pathways connecting ...the nasal passages to the brain. The purpose of this research was to enhance intranasal drug targeting to the CNS by incorporating a vasoconstrictor phenylephrine (PHE) into nasal formulations containing therapeutic neuropeptides hypocretin-1 (HC) or the dipeptide L-Tyr-D-Arg (D-KTP). Concentrations in CNS tissues, peripheral tissues, and blood were determined at 30 min following intravenous or intranasal administration of (125)I-labeled neuropeptides with and without PHE. Compared with intranasal controls, inclusion of 1% PHE in nasal formulations significantly reduced absorption into the blood for HC (65% reduction) and D-KTP (56% reduction), whereas it significantly increased deposition into the olfactory epithelium by approximately 3-fold for both. PHE (1%) significantly increased delivery to the olfactory bulbs for HC (2.1-fold) and D-KTP (3.0-fold), whereas it significantly reduced concentrations in the trigeminal nerve for HC (65% reduction) and D-KTP (39% reduction) and in most remaining brain regions by approximately 50% for both. The dramatic reduction in blood concentrations with PHE contributed to brain-to-blood concentration ratios that were significantly increased for HC throughout the brain (1.6-6.8-fold) compared with intranasal controls. For D-KTP, 1% PHE significantly increased ratios only in the olfactory bulbs (5.3-fold). With a 5% PHE formulation, D-KTP ratios were significantly increased to additional brain areas (1.5-16-fold). Vasoconstrictor nasal formulations may have particular relevance for CNS therapeutics with adverse side effects where it would be advantageous to limit systemic exposure.
Addiction to substances such as alcohol, cocaine, opioids, and methamphetamine poses a continuing clinical and public challenge globally. Despite progress in understanding substance use disorders, ...challenges remain in their treatment. Some of these challenges include limited ability of therapeutics to reach the brain (blood–brain barrier), adverse systemic side effects of current medications, and importantly key aspects of addiction not addressed by currently available treatments (such as cognitive impairment). Inability to sustain abstinence or seek treatment due to cognitive deficits such as poor decision-making and impulsivity is known to cause poor treatment outcomes. In this review, we provide an evidenced-based rationale for intranasal drug delivery as a viable and safe treatment modality to bypass the blood–brain barrier and target insulin to the brain to improve the treatment of addiction. Intranasal insulin with improvement of brain cell energy and glucose metabolism, stress hormone reduction, and improved monoamine transmission may be an ideal approach for treating multiple domains of addiction including memory and impulsivity. This may provide additional benefits to enhance current treatment approaches.
Background
Alzheimer’s disease, the most common cause of dementia, goes unrecognized in half of patients presenting to healthcare providers and is associated with increased acute care utilization. ...Routine cognitive screening of older adults in healthcare settings could improve rates of dementia diagnosis and patterns of healthcare utilization.
Objective
To evaluate the impact of screening positive for cognitive impairment on provider action in primary and specialty care practices and patient healthcare utilization.
Design
Individuals asymptomatic for cognitive impairment completed cognitive screening with the Mini-Cog (MC). Outcomes included MC screen-positive rates, provider follow-up actions, and healthcare utilization for all participants over a period of 36 months (18 months prior to and following MC screening). Data were extracted from the electronic medical record (EMR). Healthcare provider interventions and healthcare utilization for screen-positive and -negative groups, before and after screening, were compared.
Participants
Primary and specialty care patients (
n
= 787) aged ≥ 65 without history of cognitive impairment seen in HealthPartners, an integrated healthcare system in Minnesota and Western Wisconsin.
Key Results
In primary care and neurology practices combined, over the entire 36-month study window, individuals screening positive showed 32% higher rates of ED visits (
p
< 0.05) pre and post-screening compared to those screening negative. Screen positive also showed 39% higher rates of hospitalizations pre-screening (
p
< 0.05) and 58% higher rates post-screening (
p
< 0.01). While screen-detected cognitive impairment was associated with some relevant provider follow-up action in 32% of individuals, subsequent healthcare utilization did not change between the 18-month pre- and post-screening periods.
Conclusion
Despite being associated with higher rates of healthcare utilization, screening positive on the MC led to a change in provider action in a minority of cases and did not reduce post-screening healthcare utilization. Screening for cognitive impairment alone is not sufficient to alter patterns of provider practice or patient healthcare utilization.
Insulin deficiency in type I diabetes may lead to cognitive impairment, cerebral atrophy and white matter abnormalities. We studied the impact of a novel delivery system using intranasal insulin ...(I-I) in a mouse model of type I diabetes (streptozotocin-induced) for direct targeting of pathological and cognitive deficits while avoiding potential adverse systemic effects. Daily I-I, subcutaneous insulin (S-I) or placebo in separate cohorts of diabetic and non-diabetic CD1 mice were delivered over 8 months of life. Radio-labelled insulin delivery revealed that I-I delivered more rapid and substantial insulin levels within the cerebrum with less systemic insulin detection when compared with S-I. I-I delivery slowed development of cognitive decline within weekly cognitive/behavioural testing, ameliorated monthly magnetic resonance imaging abnormalities, prevented quantitative morphological abnormalities in cerebrum, improved mouse mortality and reversed diabetes-mediated declines in mRNA and protein for phosphoinositide 3-kinase (PI3K)/Akt and for protein levels of the transcription factors cyclic AMP response element binding protein (CREB) and glycogen synthase kinase 3β (GSK-3β) within different cerebral regions. Although the murine diabetic brain was not subject to cellular loss, a diabetes-mediated loss of protein and mRNA for the synaptic elements synaptophysin and choline acetyltransferase was prevented with I-I delivery. As a mechanism of delivery, I-I accesses the brain readily and slows the development of diabetes-induced brain changes as compared to S-I delivery. This therapy and delivery mode, available in humans, may be of clinical utility for the prevention of pathological changes in the diabetic human brain.