Intranasal delivery of erythropoietin plus insulin-like growth factor–I for acute neuroprotection in stroke

Fletcher, Lauren; Kohli, Sanjivan; Sprague, Shane; Scranton, Robert A.; Lipton, Stuart A.; Parra, Augusto; Jimenez, David F.; Digicaylioglu, Murat

doi:10.3171/2009.2.jns081199

Cited by 89 publications

(71 citation statements)

References 26 publications

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“…Remarkably, IN GUO treatment that was initiated immediately after ischemia onset prevented behavior impairment and decreased brain infarct volume with a dose almost seven times lower than the effective dose for IP administration [11,12]. This effective result of IN compared to systemic administration was also observed for other neuroprotective drugs against ischemia damage [29,30] .…”

Section: Discussionmentioning

confidence: 74%

“…Hence, the IN route of administration may be a particularly attractive drug delivery method to manage cerebrovascular diseases, such as stroke [27,28]. Accordingly, therapeutic proteins and other molecules were delivered to ischemic brains, suggesting that IN administration is clearly a promising route for stroke therapy [29][30][31]. Thus, IN GUO administration could offer a potential means of improved delivery to the brain.…”

Section: Introductionmentioning

confidence: 99%

“…Several works have demonstrated transport of macromolecules across the nasal epithelia, sometimes faster and higher than the conventional intravascular pathway [27][28][29][30][31]. Currently, it is thought that substances that are able to cross the nasal epithelial barrier can reach the brain through components associated with the olfactory and trigeminal nerves after IN administration.…”

Section: Introductionmentioning

confidence: 99%

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Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats

Ramos

Müller

Rocha

et al. 2015

Purinergic Signalling

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In addition to its intracellular roles, the nucleoside guanosine (GUO) also has extracellular effects that identify it as a putative neuromodulator signaling molecule in the central nervous system. Indeed, GUO can modulate glutamatergic neurotransmission, and it can promote neuroprotective effects in animal models involving glutamate neurotoxicity, which is the case in brain ischemia. In the present study, we aimed to investigate a new in vivo GUO administration route (intranasal, IN) to determine putative improvement of GUO neuroprotective effects against an experimental model of permanent focal cerebral ischemia. Initially, we demonstrated that IN [ 3 H] GUO administration reached the brain in a dose-dependent and saturable pattern in as few as 5 min, presenting a higher cerebrospinal GUO level compared with systemic administration. IN GUO treatment started immediately or even 3 h after ischemia onset prevented behavior impairment. The behavior recovery was not correlated to decreased brain infarct volume, but it was correlated to reduced mitochondrial dysfunction in the penumbra area. Therefore, we showed that the IN route is an efficient way to promptly deliver GUO to the CNS and that IN GUO Purinergic Signalling (2016) 12:149-159 DOI 10.1007 Denise Barbosa Ramos and Gabriel Cardozo Muller contributed equally as first authors.Electronic supplementary material The online version of this article (doi:10.1007/s11302-015-9489-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats

Ramos

Müller

Rocha

et al. 2015

Purinergic Signalling

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“…For example, insulin-like growth factor I has been reported to mediate the protective effects of exercise against the progression of inherited Purkinje cell degeneration in the cerebellum (3). This growth factor helps the neural protection in culture or in vivo against proapoptotic insults (7,8). Thus insulin-like growth factor I, present in abundance in the plasma under exercised conditions, would exert a neuroprotective effect when it passes through the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 99%

Chronic treadmill exercise in rats delicately alters the Purkinje cell structure to improve motor performance and toxin resistance in the cerebellum

Huang

Lin

Cho

et al. 2012

Journal of Applied Physiology

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CJ. Chronic treadmill exercise in rats delicately alters the Purkinje cell structure to improve motor performance and toxin resistance in the cerebellum. J Appl Physiol 113: 889-895, 2012. First published July 26, 2012 doi:10.1152/japplphysiol.01363.2011.-Although exercise usually improves motor performance, the underlying cellular changes in the cerebellum remain to be elucidated. This study aimed to investigate whether and how chronic treadmill exercise in young rats induced Purkinje cell changes to improve motor performance and rendered the cerebellum less vulnerable to toxin insults. After 1-wk familiarization of treadmill running, 6-wk-old male Wistar rats were divided into exercise and sedentary groups. The exercise group was then subjected to 8 wk of exercise training at moderate intensity. The rotarod test was carried out to evaluate motor performance. Purkinje cells in cerebellar slices were visualized by lucifer yellow labeling in single neurons and by calbindin immunostaining in groups of neurons. Compared with sedentary control rats, exercised rats not only performed better in the rotarod task, but also showed finer Purkinje cell structure (higher dendritic volume and spine density with the same dendritic field). The exercise-improved cerebellar functions were further evaluated by monitoring the long-lasting effects of intraventricular application of OX7-saporin. In the sedentary group, OX7-saporin treatment retarded the rotarod performance and induced ϳ60% Purkinje cell loss in 3 wk. As a comparison, the exercise group showed much milder injuries in the cerebellum by the same toxin treatment. In conclusion, exercise training in young rats increased the dendritic density of Purkinje cells, which might play an important role in improving the motor performance. Furthermore, as Purkinje cells in the exercise group were relatively toxin resistant, the exercised rats showed good motor performance, even under toxin-treated conditions. morphology; OX7-saporin; two-photon microscopy; running; motor function THE RELATIONSHIP BETWEEN PHYSICAL activity and brain functions has been widely investigated. In particular, physical activity in older subjects benefits their mental health by protecting the brain against age-related deterioration (6). Many exercise studies primarily focus on brain structural and functional changes related to cognitive improvements (15), with relatively few studies focusing on the motor performance. Consequently, although connections between cognitive deficits and age-associated brain differences have been elucidated, relationships with motor performance are less well understood. Interestingly, aging impacts brain structures and associated behaviors differentially, with the cerebellum showing earlier senescence than the hippocampus (31). As physically active older adults require less error monitoring and show improvements in motor performance (26), it is desirable to explore the beneficial effects of exercise on the cerebellum. Purkinje cells in aged rats show pronounced dendrite degener...

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“…Numerous previous studies regarding protein and peptide delivery to the CNS have indicated that proteins such as NGF (Chen et al, 1998;De Rosa et al, 2005), insulin (Francis et al, 2008;Renner et al, 2012;Shemesh et al, 2012), and IGF-1 (Fletcher et al, 2009;Liu et al, 2001;Thorne et al, 2004) preferentially enter the CNS through extracellular channels between the olfactory receptor neuron (ORN) axons and the olfactory ensheathing cells protecting them from the cribiform plate (Dhuria et al, 2010;Wu et al, 2008). As a result, it is probable that preferentially depositing substances onto the olfactory epithelium where ORN axons originate would increase the amount of D1-D2 interfering peptide delivered to the CNS while minimizing loss to the periphery.…”

Section: Discussionmentioning

confidence: 99%

Intranasal Delivery of a Peptide with Antidepressant-Like Effect

Brown

Liu

2014

Neuropsychopharmacol

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A critical issue in drug development is developing effective, noninvasive delivery routes to the central nervous system (CNS). Major depressive disorder (MDD) is an illness associated with significant morbidity. Even with multiple antidepressant trials, 10-15% of patients continue to experience persistent depressive symptoms. We previously developed an interfering peptide that has antidepressant-like effects in rats when injected directly into the brain. To be clinically viable, it must demonstrate efficacy via a noninvasive administration route. We report here that the interfering peptide designed to disrupt the interaction between the D1 and D2 dopamine receptors can be delivered to relevant brain areas using the Pressurized Olfactory Device (POD), a novel intranasal delivery system developed by Impel NeuroPharma. We validate this delivery method by demonstrating that, at doses X1.67 nmol/g, the D1-D2 interfering peptide has a significant antidepressant-like effect comparable to that of imipramine in the forced swimming test (FST), a common test for antidepressant efficacy. The antidepressant-like effect of the interfering peptide can be detected for 2 h after intranasal administration. Furthermore, we show that the interfering peptide disrupts the D1-D2 interaction and it can be detected in the prefrontal cortex after intranasal administration. This study provides strong preclinical support for intranasal administration of the D1-D2 interfering peptide as a new treatment option for patients suffering from MDD.

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Intranasal delivery of erythropoietin plus insulin-like growth factor–I for acute neuroprotection in stroke

Abstract: The data demonstrate that intranasal EPO plus IGF-I penetrates into the brain more efficiently than other drug delivery methods and could potentially provide a fast and efficient treatment to prevent chronic effects of stroke.

Cited by 89 publications

References 26 publications

Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats

Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats

Chronic treadmill exercise in rats delicately alters the Purkinje cell structure to improve motor performance and toxin resistance in the cerebellum

Intranasal Delivery of a Peptide with Antidepressant-Like Effect

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