The Intranasal Administration of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP): A New Rodent Model to Test Palliative and Neuroprotective Agents for Parkinson's disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting approximately 1% of the population older than 60 years. Classically, PD is considered to be a motor system disease and its diagnosis is based on the presence of a set of cardinal motor signs that are consequence of a pronounced death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Nowadays there is considerable evidence showing that non-dopaminergic degeneration also occurs in other brain areas which seems to be responsible for the deficits in olfactory, emotional and memory functions that precede the classical motor symptoms in PD. Dopamine-replacement therapy has dominated the treatment of PD and although the currently approved antiparkinsonian agents offer effective relief of the motor deficits, they have not been found to alleviate the non-motor features as well as the underlying dopaminergic neuron degeneration and thus drug efficacy is gradually lost. Another major limitation of chronic dopaminergic therapy is the numerous adverse effects such as dyskinesias, psychosis and behavioral disturbance. The development of new therapies in PD depends on the existence of representative animal models to facilitate the evaluation of new pharmacological agents before they are applied in clinical trials. We have recently proposed a new experimental model of PD consisting of a single intranasal (i.n.) administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 1 mg/nostril) in rodents. Our findings demonstrated that rats and mice treated intranasally with MPTP suffer impairments in olfactory, cognitive, emotional and motor functions conceivably analogous to those observed during different stages of PD. Such infusion causes time-dependent loss of tyrosine hydroxylase in the olfactory bulb and SNc, resulting in significant dopamine depletion in different brain areas. We have also identified some pathogenic mechanisms possibly involved in the neurodegeneration induced by i.n. administration of MPTP including mitochondrial dysfunction, oxidative stress, activation of apoptotic cell death mechanisms and glutamatergic excitotoxicity. Therefore, the present review attempts to provide a comprehensive picture of the i.n. MPTP model and to highlight recent findings from our group showing its potential as a valuable rodent model for testing novel drugs that may provide alternative or adjunctive treatment for both motor and non-motor symptoms relief with a reduced side-effect profile as well as the discovery of compounds to modify the course of PD.

A new dopaminergic nigro-olfactory projection

“…Prior studies had already demonstrated degeneration of dopaminergic SNc neurons upon application of MPTP into the nasal cavity [44], however, it remained unclear whether the toxicity was effected by systemic distribution of the pro-drug MPTP via the blood circulation [44].…”

Intranasal Administration of Neurotoxicants in Animals: Support for the Olfactory Vector Hypothesis of Parkinson’s Disease

“…administration of MPTP in rodents correlated with a marked loss of TH staining in the olfactory bulb, SNpc, and striatum, resulting in significant DA depletion in the olfactory bulb, prefrontal cortex, and striatum (Prediger et al 2006(Prediger et al , 2009a(Prediger et al , b, 2010(Prediger et al , 2011Moreira et al 2010). The levels of DA metabolites DOPAC and HVA were also significantly decreased in these brain structures.…”

“…For this reason, we recently developed an experimental rodent model of PD consisting of a single i.n. administration of MPTP (for review, see Prediger et al 2011). Interestingly, at the same time that our group published the first paper describing the i.n.…”

“…To address this problem, we have studied the occurrence of olfactory, emotional, cognitive, and motor alterations in young adult Wistar rats (3 months old) and C57BL/6 mice (5-6 months old) over the course of onemonth period after a single bilateral i.n. administration of MPTP (0.1 or 1 mg/nostril) (Prediger et al 2006(Prediger et al , 2011Moreira et al 2010). Briefly, the animals were lightly anaesthetized with isoflurane 0.96% (0.75 CAM) using a vaporizer system (SurgiVet Inc., WI, USA).…”

Animal models of neurodegenerative diseases

“…More recently, Prediger et al showed that intranasal infusion of MPTP in rodents causes motor impairments and olfactory and cognitive deficits that resemble the different stages of PD. 65,66 Rotenone, a pesticide used in farming, is also highly lipophilic and easily crosses the blood brain barrier. Rotenone is a high-affinity inhibitor of mitochondrial complex I, but unlike MPTP, its entrance into cells is not dependent on a specific transporter.…”