The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. Substantia nigra is Latin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta.
Dopamine is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.
The nigrostriatal pathway is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum in the forebrain. It is one of the four major dopamine pathways in the brain, and is critical in the production of movement as part of a system called the basal ganglia motor loop. Dopaminergic neurons of this pathway release dopamine from axon terminals that synapse onto GABAergic medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), located in the striatum.
Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein interactions. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.
Arvid Carlsson was a Swedish neuropharmacologist who is best known for his work with the neurotransmitter dopamine and its effects in Parkinson's disease. For his work on dopamine, Carlsson was awarded the Nobel Prize in Physiology or Medicine in 2000, together with Eric Kandel and Paul Greengard.
A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have found use in treating schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetics used in the treatment of nausea and vomiting.
Intrinsically photosensitive retinal ganglion cells (ipRGCs), also called photosensitive retinal ganglion cells (pRGC), or melanopsin-containing retinal ganglion cells (mRGCs), are a type of neuron in the retina of the mammalian eye. The presence of ipRGCs was first suspected in 1927 when rodless, coneless mice still responded to a light stimulus through pupil constriction, This implied that rods and cones are not the only light-sensitive neurons in the retina. Yet research on these cells did not advance until the 1980s. Recent research has shown that these retinal ganglion cells, unlike other retinal ganglion cells, are intrinsically photosensitive due to the presence of melanopsin, a light-sensitive protein. Therefore they constitute a third class of photoreceptors, in addition to rod and cone cells.
Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipexole is a dopamine agonist of the non-ergoline class.
A dopamine agonist(DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used in the treatment of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. The use of dopamine agonists is associated with impulse control disorders and dopamine agonist withdrawal syndrome (DAWS).
The pars compacta (SNpc) is a portion of the substantia nigra, located in the midbrain. It is formed by dopaminergic neurons and located medial to the pars reticulata. Parkinson's disease is characterized by the death of dopaminergic neurons in this region.
Rasagiline is an irreversible inhibitor of monoamine oxidase-B used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases.
Melatonin receptors are G protein-coupled receptors (GPCR) which bind melatonin. Three types of melatonin receptors have been cloned. The MT1 (or Mel1A or MTNR1A) and MT2 (or Mel1B or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype MT3 (or Mel1C or MTNR1C) has been identified in amphibia and birds. The receptors are crucial in the signal cascade of melatonin. In the field of chronobiology, melatonin has been found to be a key player in the synchrony of biological clocks. Melatonin secretion by the pineal gland has circadian rhythmicity regulated by the suprachiasmatic nucleus (SCN) found in the brain. The SCN functions as the timing regulator for melatonin; melatonin then follows a feedback loop to decrease SCN neuronal firing. The receptors MT1 and MT2 control this process. Melatonin receptors are found throughout the body in places such as the brain, the retina of the eye, the cardiovascular system, the liver and gallbladder, the colon, the skin, the kidneys, and many others. In 2019, X-ray crystal and cryo-EM structures of MT1 and MT2 were reported.
Sundowning, or sundown syndrome, is a neurological phenomenon associated with increased confusion and restlessness in people with delirium or some form of dementia. It is most commonly associated with Alzheimer's disease but also found in those with other forms of dementia. The term "sundowning" was coined by nurse Lois K. Evans in 1987 due to the timing of the person's increased confusion beginning in the late afternoon and early evening. For people with sundown syndrome, a multitude of behavioral problems begin to occur and are associated with long term adverse outcomes. Sundowning seems to occur more frequently during the middle stages of Alzheimer's disease and mixed dementia and seems to subside with the progression of the person's dementia. People are generally able to understand that this behavioral pattern is abnormal. Research shows that 20–45% of people with Alzheimer's will experience some variation of sundowning confusion. However, despite lack of an official diagnosis of sundown syndrome in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), there is currently a wide range of reported prevalence.
BTS 74,398 is a centrally acting stimulant drug which was developed for the treatment of Parkinson's disease. It inhibits the synaptic reuptake of dopamine, serotonin and noradrenaline, making it a triple reuptake inhibitor. It was effective in animal models of Parkinson's disease, but was unsuccessful in human trials.
Ann Martin Graybiel is an Institute Professor and a faculty member in the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology. She is also an investigator at the McGovern Institute for Brain Research. She is an expert on the basal ganglia and the neurophysiology of habit formation, implicit learning, and her work is relevant to Parkinson's disease, Huntington's disease, obsessive–compulsive disorder, substance abuse and other disorders that affect the basal ganglia.
UWA-101 is a phenethylamine derivative invented by Dr Matthew Piggott at the University of Western Australia, and researched as a potential treatment for Parkinson's disease. Its chemical structure is very similar to that of the illegal drug MDMA, the only difference being the replacement of the α-methyl group with an α-cyclopropyl group. MDMA has been found in animal studies and reported in unauthorised human self-experiments to be effective in the short-term relief of side-effects of Parkinson's disease therapy, most notably levodopa-induced dyskinesia. However the illegal status of MDMA and concerns about its potential for recreational use, neurotoxicity and potentially dangerous side effects mean that it is unlikely to be investigated for medical use in this application, and so alternative analogues were investigated.
Kochupurackal P. Mohanakumar is an Indian chemical biologist, neuroscientist and the director of Inter University Centre for Biomedical Research and Super Specialty Hospital, Kottayam. He is a former chief scientist at the Indian Institute of Chemical Biology and is known for his studies on Parkinson's disease and Huntington’s disease. The Department of Biotechnology of the Government of India awarded him the National Bioscience Award for Career Development, one of the highest Indian science awards, for his contributions to biosciences in 2000.
D. James "Jim" Surmeier, an American neuroscientist and physiologist of note, is the Nathan Smith Davis Professor and Chair in the Department of Physiology at Northwestern University Feinberg School of Medicine. His research is focused on the cellular physiology and circuit properties of the basal ganglia in health and disease, primarily Parkinson's and Huntington's disease as well as pain.
The Shake It Up Australia Foundation (SIUAF) is an Australian non-for-profit foundation founded in 2011 by Clyde and Greg Campbell. It is partnered with the Michael J. Fox Foundation (MJFF) to achieve the foundations primary aims of “promoting and funding Parkinson’s disease research in Australia to slow, stop and cure the disease”. Together MJFF and SIUAF are the largest non-government funders of Parkinson's research across multiple institutes in Australia. Since its founding, the foundation has co-founded 38 Parkinson's research projects across 12 institutes to the value of over $10.8 million. The foundation's funding model ensures that 100% of proceeds goes towards Parkinson's research in Australia. This is possible due to the founding directors covering all overhead costs and expenses. In January 2019, Shake It Up are one of the partner organisation in the Australian Parkinson's Mission which was awarded a $30 million-dollar grant to test repurposed drugs in clinical trials.
Michal Rivlin is a Senior Scientist and Sara Lee Schupf Family Chair in Neurobiology at the Weizmann Institute of Science. She was awarded the 2019 Blavatnik Awards for Young Scientists for her research on the neuronal circuitry of the retina.
