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Abstract. Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. It affects the locomotor system, leading to a final severe disability through degeneration of dopaminergic neurons. Despite several therapeutic approaches used, no treatment has been proven to be effective; however, cell therapy may be a promising therapeutic method. In addition, the use of the intranasal (IN) route has been advocated for delivering various therapies to the brain. In the present study, the IN route was used for administration of mesenchymal stem cells (MSCs) in a mouse model of PD, with the aim to evaluate IN delivery as an alternative route for cell based therapy administration in PD. The PD model was developed in C57BL/6 mice using intraperitoneal rotenone administration for 60 consecutive days. MSCs were isolated from the mononuclear cell fraction of pooled bone marrow from C57BL/6 mice and incubated with micrometer-sized iron oxide (MPIO) particles. For IN administration, we used a 20 µl of 5x10 5 cell suspension. Neurobehavioral assessment of the mice was performed, and after sacrifice, brain sections were stained with Prussian blue to detect the MPIO-labeled MSCs. In addition, immunohistochemical evaluation was conducted to detect tyrosine hydroxylase (TH) antibodies in the corpus striatum and dopaminergic neurons in the substantia nigra pars compacta (SNpc). The neurobehavioral assessment revealed progressive deterioration in the locomotor functions of the rotenone group, which was improved following MSC administration. Histopathological evaluation of brain sections in the rotenone+MSC group revealed successful delivery of MSCs, evidenced by positive Prussian blue staining. Furthermore, rotenone treatment led to significant decrease in dopaminergic neuron number in SNpc, as well as similar decrease in the corpus striatum fiber density. By contrast, in animals receiving IN administration of MSCs, the degeneration caused by rotenone treatment was significantly counteracted. In conclusion, the present study validated that IN delivery of MSCs may be a potential safe, easy and cheap alternative route for stem cell treatment in neurodegenerative disorders.

Alzheimer's disease (AD) is recognized as a major health hazard that mostly affects people older than 60 years. AD is one of the biggest medical, economic, and social concerns to patients and their caregivers. AD was ranked as the 5 th leading cause of global deaths in 2016 by the World Health Organization (WHO). Many drugs targeting the production, aggregation, and clearance of Ab plaques failed to give any conclusive clinical outcomes. This mainly stems from the fact that AD is not a disease attributed to a single-gene mutation. Two hallmarks of AD, Ab plaques and neurofibrillary tangles (NFTs), can simultaneously induce other AD etiologies where every pathway is a loop of consequential events. Therefore, the focus of recent AD research has shifted to exploring other etiologies, such as neuroinflammation and central hyperexcitability. Neuroinflammation results from the hyperactivation of microglia and astrocytes that release pro-inflammatory cytokines due to the neurological insults caused by Ab plaques and NFTs, eventually leading to synaptic dysfunction and neuronal death. This review will report the failures and side effects of many anti-Ab drugs. In addition, emerging treatments targeting neuroinflammation in AD, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and receptor-interacting serine/threonine protein kinase 1 (RIPK1), that restore calcium dyshomeostasis and microglia physiological function in clearing Ab plaques, respectively, will be deliberately discussed. Other novel pharmacotherapy strategies in treating AD, including disease-modifying agents (DMTs), repurposing of medications used to treat non-AD illnesses, and multi target-directed ligands (MTDLs) are also reviewed. These approaches open new doors to the development of AD therapy, especially combination therapy that can cater for several targets simultaneously, hence effectively slowing or stopping AD.

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