Researchers from the college of Pharmaceutical Sciences in China have recently studied a compound that enhances neuronal recovery in a rat model of Parkinson’s disease (Parkinson 6 OHDA). Parkinson’s disease is a chronic disorder of the central nervous system, caused primarily by the progressive loss of dopaminergic neurons of the Substantia nigra region of the brain that play an important role in reward, addiction and movement.
The researchers administered intranasally phospholipid-based gelatin nanoparticules loaded with neuropeptide Substance P to rat models of Parkinson’s disease and monitored the rotational behaviour of the animals, as well as their levels of tyrosine hydroxylase, phosphorylated c-Jun protein and Caspase-3 expressed in their substantia nigra. This Neuropeptide Substance P (SP) is involved in the regulation of many biological processes and is a major mediator of neuroimmunomodulatory activities and neurogenic inflammation. In vitro experiments had already shown that SP can protect dopamine neurons from toxicity, decrease neuron apoptosis and enhance cell growth.
In Parkinson’s disease patients, the expression of SP and dopamine is significantly reduced in the Substantia Nigra, which results in an increase death of dopaminergic neurons and a limited expression of tyrosine hydroxylase. The researchers chose to use hemiparkinsonian rats with a substantia nigra partially damaged by 6-OHDA to model Parkinson’s disease. 6-OHDA injections into the brains of rats induce apoptosis of dopaminergic neurons and reduce the expression of SP – mimicking the symptoms of Parkinson’s disease. The 6-OHDA model is a valuable tool frequently used in rodents, mostly to investigate motor and biochemical dysfunctions in Parkinson’s disease. It mimics the human situation closely and has the advantage of presenting side-biased motor impairments and being very sensitive to dopamine agonists. More subtle models of partial dopaminergic degeneration have been developed to reveal finer motor deficits but the 6-OHDA model remains the traditional model for testing Parkinson’s therapies, especially those intended to increase dopamine levels in the striatum.
SP plays an important role in the recovery of diseased dopaminergic neuron through the deactivation of the JNK pathway – one of the important pathways leading to dopamine neuronal apoptosis in the Substantia negra – and decrease in neuronal apoptosis. However, as a macromolecule, it is not likely that SP administrated orally or intravenously could cross the blood-brain barrier. The current study investigated whether SP can be delivered into the CNS intranasally thanks to gelatin nanoparticles to play a neuroprotective role by inhibiting activation of JNK pathway and decrease dopaminergic neuron apoptosis.
This preclinical study found that SP can be effectively delivered into the damaged Substantia negra region through the nose-to-brain pathway and efficiently inhibit dopaminergic neuron apoptosis through the JNK pathway, allowing for hemiparkinsonian rats to recover.
This study will hopefully lead to clinical trial to help the 1-2% of the population above the age of 60 affected by Parkinson’s disease that remains a difficult disease for clinical management.
Syncrosome is an Efficacy Characterization preclinical CRO that offers relevant disease models, cutting-edge techniques and a comprehensive background of physiopathology to assist drug discovery companies. Syncrosome is specialized in Parkison preclinical evaluation and uses 2 differents 6-OHDA rodent models (early and late stage), for drug screening and efficacy testing. Other Parkinson models also available.
Key words: Parkinson preclinical, preclinical CRO, preclinical study, animal model, dyskinesia rat, 6-OHDA rat, rodent dopaminergic neurons, Substantia nigra, neuroprotection, blood brain barrier, Parkinson animal model, MPTP, MPP+