Substantia Nigra

Parkinson disease (PD) is one of the most common neurologic disorders. and it affects approximately 1% of individuals older than 60 years old. Parkinson’s disease is a condition that progresses slowly by treatment. In addition, loss of pigmented dopaminergic neurons of the substantianigra pars compacta and the presence of Lewy bodies and Lewyneurites are the two major neuropathologic findings in Parkinson disease (Hauser, 2016).

Parkinson 's disease is a progressive neurologic degenerative disease of the Central Nervous system. The brain produces Dopamine and Norepinephrine, which are chemicals needed for smooth muscle movement and coordination, heart rate, and blood pressure. Dopamine and Norepinephrine are released by basal ganglions that are produced in a bundle of nerve cells in the brainstem called substantia nigra. In Parkinson 's patients, the substantia nigra are destroyed and neither of the chemicals can be released into the body. (3) The decrease in Norepinephrine causes heart arrhythmia and low blood pressure, causing the person to get dizzy upon standing or tire easily. The lack of Dopamine, the smooth muscle movement and coordination controller is now gone, or significantly decreased, resulting in the first signs of Parkinson’s disease, pill-rolling, a one handed tremor and a decreased appetite. (2)

Parkinson’s disease is a “neurodegenerative disorder of the basal nuclei due to insufficient secretion of the neurotransmitter dopamine” (Marieb & Hoehn, 2013, p. G-17). The cause of Parkinson’s disease is unknown, but many factors play a role in the development of Parkinson’s disease. One factor that has been found in an individual who has Parkinson’s disease causes over activity of targeted dopamine-deprived basal nuclei. This over activity is caused by the breakdown of neurons that release dopamine in the substantia nigra (Marieb & Hoehn, 2013). Another factor that is present in a person who has Parkinson’s disease, is the presence of lewy bodies in the brain stem ("What is lbd?," 2014). Lewy bodies are unusual

AD is a progressive age-related neurodegenerative disorder that poses increasing challenges to the global healthcare system and economic development. AD is characterized by extracellular neurotic plaques composed of Aβ deposits and intracellular neurofibrillary tangles composed of hyperphosphorylated tau with progressive loss of synapses in the brain [1]. Evidence demonstrates a potential link between oxidative stress, mitochondrial dysfunction and AD development [2]. Oxidative damage has been known to occur at a very early stage of AD even prior to Aβ plaque formation and the onset of symptoms [3, 4, 5]. Several cellular changes by oxidative stresses have been related with Aβ plaques formation and pathophysiological events of AD [6].

Parkinson disease (PD), also referred to as Parkinson’s disease and paralysis agitans, is a progressive neurodegenerative disease that is the third most common neurologic disorder of older adults. It is a debilitating disease affecting motor ability and is characterized by four cardinal symptoms: tremor rigidity, bradykinesia or kinesis (slow movement/no movement), and postural instability. Most people have primary, or idiopathic, disease. A few patients have secondary parkinsonian symptoms from conditions such as brain tumors and certain anti-psychotic drugs.

Parkinson's Disease is a literally crippling neurodegenerative disorder, manifested in about 1% of the aged population. People who have Parkinson's Disease gradually lose control of their movements; specific symptoms include, "tremor, slowness of movement, stiffness, difficulty in walking, and loss of balance." (1) Evidence strongly suggests that Parkinson's Disease is the result of severe cell loss in the substantia nigra. This brain structure is principally involved in the production of dopamine. (2) Dopamine, among other functions, is the neurotransmitter involved in initiation of movement. Hence, the link between dopaminergic cell loss and cessation of voluntary movement, as manifested

These deficits increase during the course of the disease and are due to loss of dopamine-secreting neurons in the motor circuits in the basal ganglia which are necessary for control and coordination of movements. The symptoms displayed because of this are: bradykinesia, resting tremor, rigidity of muscles and impaired posture (Millage, Vesey, Finkelstein, & Anheluk, 2017). Research indicates that exercise modalities can improve both motor and non-motor aspects of PD (Dashtipour et al., 2015).

A. SIGNIFICANCE. Our goal is to screen chemical libraries to identify compounds that modulate mitochondrial transport in hippocampal and cortical neurons. This study is significant in four ways: (1) There is an urgent need to develop CNS (Central Nervous System) active drugs. CNS disorders are not only staggeringly complex but are poorly treated diseases (Palmer and Stephenson, 2005). In the United States alone the annual cost for stroke, depression, Schizophrenia and Alzheimer’s disease are currently estimated to be over $250 billion annually (Pangalos et al., 2007). Despite the advances in translational medicine and pharmaceutical research little progress has been made in developing CNS therapeutics. Improving CNS drug discovery efforts is an urgent goal as an estimated 1.5 billion people suffer from CNS-related diseases worldwide. Unfortunately only a handful of new drugs have been brought to the market with very few in the pharmaceutical pipeline (Kissinger, 2011; Schoepp, 2011; Abbot, 2011). The majority of pharmaceutical companies have recently announced a shift from supporting internal drug discovery efforts in favor of academic and government partnerships (Schoepp, 2011). At Scripps Florida we have close interaction of state of the art high throughput small molecule screening and cutting-edge neuroscience research. Thus we are in a unique position to address the challenges in developing CNS therapeutics. (2) Mitochondrial dysfunction is part of the pathophysiology of

There are hundreds of neurodegenerative diseases (NDD) and the etiology for most of the random conditions remain a universal mystery (Nieoullon 2011). A deterioration of specific functions of the neuron cells of the central nervous system is the most common characteristic of NDD. Neurons are responsible for transmitting essential information to other nerve, muscle and glandular cells (Przedborksi, Jackson-Lewis 2003). Emerging research has recently identified mitochondrial dysfunction as a recurrent elemental link in numerous neurodegenerative disorders (Ghano,

Besides the appearance of episodic focal inflammatory lesions, there is a more generalized and progressive disease process that results in slow axonal , neuronal degeneration and subsequent accumulation of neurologic disabilities. The pathogenesis of this neurodegenerative process is aurged to the mitochondrial dysfunction which could be a key contributing mechanism ( Su et al., 2013)

The pathology behind PDD is a dopaminergic neuronal loss in the substantia nigra and the presence of Lewy bodies made up of α-synuclein in the cell bodies and processes of the neurons that are left over (Rongve, Dauer). The dopaminergic neurons in the substantia nigra are being lost or inhibited by the production of the misfolded proteins resulting in the lewy bodies. The neurons of the substantia nigra are thought to make up the nigrostriatal pathway, thus their destruction would result in loss of dopamine up to the striatum, made up of the caudate nucleus and putamen. This loss of sufficient dopamine to the striatum of the basal ganglia is what is causing most of the motor movement symptoms seen in PD patients (Dauer). My grandpa used to be a police officer, and I have always perceived him as this big tough guy who could take on anything. After he got older and his PD developed, his movements got much slower and I saw him become this timid man who was unsure

For studies involving Parkinson’s Disease, mice and non-human primates are primarily used as models. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been previously shown to selectively target and breakdown nigrostriatal dopaminergic neurons and cause Parkinson’s-like symptoms in primates within a few days (McCrodden, 1990). With that, the progression of the MPTP-induced Parkinson’s disease is a sped-up model of the actual disease.

PD pathology results from a degenerative process which reduces the function of dopaminergic substantia nigra (SN) neurons below a certain threshold until it manifests as clinical symptoms17. It should be noted that degeneration of the SN is not the sole location of degeneration – regions such as the locus coeruleus, raphe nuclei, basal forebrain, and frontal cortex undergo a similar process17. The pathology is still not fully understood, but the degenerative process has been found to stem from the glossopharyngeal, vagal, and olfactory cranial nerve nuclei and then ascend upwards through the brainstem18. The degeneration of these origin structures have been theorized to be responsible for the non-motor symptoms presented in PD18.

Parkinson’s disease is affected by the degeneration of dopaminergic neurons which is responsible to produce dopamine. Dopaminergic neurons have their cell bodies in substantia nigra pars compacta (SNpc) in basal ganglia (O’Sullivan and Schmitz, 2007). Basal ganglia are a collection of interconnected gray matter nuclear masses deep within the brain”. These gray matter masses are caudate, putamen, globus pallidus, subthalamic nucleus and the substantia nigra. Basal ganglia receive its input through striatum (O’Sullivan and Schmitz, 2007).

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized mainly by physical and psychological disabilities. This disorder was named after James Parkinson, an English physician who first described it as shaking palsy in 1817 (Goetz, Factr, and Weiner, 2002). Jean- Martin Charcot, who was a French neurologist, then progressed and further refined the description of the disease and identified other clinical features of PD (Goetz, Factr, and Weiner, 2002). PD involves the loss of cells that produce the neurotransmitter dopamine in a part of the brain stem called the substansia nigra, which results in several signs and symptoms (Byrd, Marks, and Starr, 2000). It is manifested clinically by tremor,