Neuroprotection in Parkinson's disease: modafinil and Δ9-tetrahydrocannabinol

Abstract

In Parkinson's disease (PD) is the output of the basal ganglia irreversibly affected due to degeneration of the neuromelanin-containing dopaminergic neurons in the substantia nigra pars compacta. This results in manifestation of symptoms including akinesia, postural instability, rigidity and resting tremors. PD is incurable, since present medications (predominantly with levodopa) do not counteract progression of the disease and long term medication is associated with declined efficacy and increased side-effects. Therefore, a better strategy aims to focus on prevention of the neuronal loss in an attempt to stop or slow down the progression of the disease. One way to achieve neuroprotection is via pharmacological interference aimed at crucial steps in the neuronal cell death process to promote neuronal survival. In this thesis neuroprotective effects are tested in an animal model for PD closely related to man. In the applied model specific lesions of the dopaminergic neurons in the substantia nigra are induced by systemic injections of the neurotoxin MPTP. The wake-promoting compound, modafinil and the psychoactive drug, Δ9-tetrahydrocannabinol (THC) are tested in this model for PD. The potential of these compounds is based on earlier studies indicating positive results in other models of neuronal damage. The neuroprotective experiments described in this thesis indicated, despite the neuroprotective potential of THC in other PD animal models, that THC was unable to protect the neurons in the MPTP induced PD animal model. Further research is needed to find the cause for this contrary result. On the other hand, the other tested compound modafinil was quite able to protect the neurons against the degeneration induced by MPTP. This was proved by increased survival of the dopaminergic neurons in the modafinil treated animals measured with tyrosine hydroxylase staining, magnetic resonance imaging and spectroscopy. Furthermore, increased levels of dopamine in the modafinil treated animals indicated the improved function of the neurons. The positive results at brain level were also reflected at behavior level as the modafinil treated animals showed a clear reduction of the parkinsonian symptoms. It can therefore be concluded that modafinil can prevent degeneration of neurons which are the underlying cause of the symptoms typical to PD. As modafinil is considered as a safe medication for human use, testing its efficacy in the clinic could be done more easily in contrast to other experimental compounds. Besides possible neuroprotective properties of modafinil and THC, experiments described in this thesis have proved their efficacy as anti-parkinson drugs. Both compounds improved motor-related behavior. Therefore, the compounds can also be of value in the current treatment spectrum against the symptoms of PD patients.