Nitric Oxide (NO)
During the 1980s, NO was identified as a critical regulatory molecule in the human body, in 1992 was named the "Molecule of the Year" by Science, and in
1998 the Nobel Prize in Physiology and Medicine was awarded for this discovery. NO has diverse roles both in normal and pathological processes including the regulation of blood pressure, neurotransmission, and macrophage defense systems.
Nitric Oxide Synthase (NOS)
NO is synthesized by three isoforms of nitric oxide synthases (NOS) found in endothelial cells (eNOS), neuronal cells (nNOS) and macrophages (iNOS), and this family of enzymes serves different functions.
Parkinson’s Disease (PD) is characterised by the neurodegeneration of the substantia nigral dopaminergic (DA) cells leading to the classic movement disorders originally described. Disease progression and the available treatments all produce their own issues. Classic rigidity and tremor will be supplemented by dyskinesias, tics and wild oscillations in uncontrolled movements or freezing. In addition, dementia, depression and psychotic symptoms frequently develop over time. There are no disease modifying therapies to slow down neurodegeneration and many of the symptoms are potentially exacerbated by drug therapy.
• Sensitivity to DA treatments leads to dyskinesias; DA agents have also been linked to lack of impulse control leading to excessive behaviours including gambling addictions, moreover, long term use of DA agents may have their own neurotoxic effects.
• Anti-cholinergic drugs to help with tremors can impair memory;
• Many antidepressants or anxiolytics have their own consequences on both movement and cognition via sedation.
Opportunity and Therapeutic Advantage
In the absence of a complete cure, an idealised therapeutic agent for PD should be neuroprotective, slow or prevent further degeneration, allow smooth motor function while inhibiting tendencies to excessive repetitive movements, thoughts or impulses due to disease or drug treatment. NOS Inhibition is ideally suited to meet these conditions via its effects on neurodegeneration and neuromodulation of the consequences of receptor activation on behaviour.
Neurodegeneration. Nitric oxide has long been implicated in neurodegenerative processes: in part through its role in oxidative stress, and its effects on normal function in a multiple pathways (alpha-synuclein, LRRK2, PARKIN) involved in neurodegeneration. Repeated studies have confirmed that blocking NO production via knock-outs or inhibition of NOS protects against neurodegeneration and other neuronal damage in animal models. In almost every known mechanism and pathway associated with neuronal toxicity excess NO activity amplifies the problem in a cumulative manner. This does not mean that NO is the cause of all neurotoxicity, but its unique role in aiding the development of the pathological changes means that it has a unique role in being able to reduce neurotoxicity via multiple cumulative effects.
Dyskinesia. The interaction between the nitric oxide system and certain neurotransmitter is well established. Nitric oxide has been shown repeatedly to modify the effects of glutamate, opiates and DA. In all cases inhibiting nNOS seems to modify excessive activity through changes in sensitisation. Data generated by NeurAxon and others suggests that nNOS inhibitors can reduce DA over-activity from receptors sensitised via DA lesions, dopamine release enhancers such as amphetamines and direct agonists such as apomorphine, all at doses which do not cause unwanted side effects such as sedation or cognitive deficits.
NOS inhibitors therefore offer a potential key series of advantages to the treatment of Parkinson’s disease via modifying effects related to motoric dysfunction, neurodegeneration and other consequences of disease and current drug therapies.
Scientific Articles About NOS
Del Bel. E et al; “Nitric oxide, a new player in l-dopa-induced dyskinesia?”, 2015, Frontiers in Bioscience, Elite, 7, 193 – 221.
Džoljic, E et al; “Why is nitric oxide important for our brain?”, Functional Neurology, 2015, 30 (3), 159-163
Solis, O et al, “Nitric oxide synthase inhibition decreases L-Dopa-induced dyskinesia and the expression of striatal molecular markers in Pitx3 aphakia mice”, 2015, Neurobiology of Disease, 73, 49-59.
Lorenc-Koci, E and Czarnecka, A; “Role of nitric oxide in the regulation of motor function. An overview of behavioral, biochemical and histological studies in animal models”, Pharmacological Reports, 2013, 65, 1043-1055.
Sammut, S et al; “Nitric oxide-soluble guanylyl cyclase signaling regulates corticostriatal transmission and short-term synaptic plasticity of striatal projection neurons recorded in vivo”, Neuropharmacology, 2010, 58 (3), 624.
Gao, H.M. et al, “Neuroinflammation and Oxidation/Nitration of a-Synuclein Linked to Dopaminergic Neurodegeneration”, 2008, Journal of Neuroscience, 28 (30), 7687-7968.