No abstract

One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke.

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.

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.

In view of the rapid preclinical development of cell-based therapies for neurodegenerative disorders, traumatic brain injury, and tumors, the safe and efficient delivery and targeting of therapeutic cells to the central nervous system is critical for maintaining therapeutic efficacy and safety in the respective disease models. Our previous data demonstrated therapeutically efficacious and targeted delivery of mesenchymal stem cells (MSCs) to the brain in the rat 6-hydroxydopamine model of Parkinson's disease (PD). The present study examined delivery of bone marrow-derived MSCs, macrophages, and microglia to the brain in a transgenic model of PD [ (Thy1) aS model] immunoreactivity. Here, we show, for the first time, intranasal delivery of cells to the brain of transgenic PD and AD mouse models. Additional work is needed to determine the optimal dosage (single treatment regimen or repeated administrations) to achieve functional improvement in these mouse models with intranasal microglia/macrophages and MSCs. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.