Neuroprotective Agents For Parkinsons Disease
Relevant preclinical studies have identified several compounds such as MLT, estrogen, nicotine, caffeine, riluzole, curcumin, aspirin, epigallocatechin-3-gallate and resveratrol, as neuroprotective agents in PD . Various prospective studies have suggested a strong association between tobacco smoking and a decreased risk of PD. Nicotine is one of the main constituents of tobacco and is known for its pharmacological effects, exerted by interaction with cholinergic nicotinic receptors in both central and peripheral nervous systems . A recent clinical trial among six male PD patients demonstrated that chronic high doses of nicotine improved motor scores, reduced dopaminergic treatment and had a potential beneficial effect on striatal dopamine transporter density . Chronic nicotine treatment partly protects against the MPTP-induced degeneration of nigrostriatal dopamine neurons in the black mouse, counteracts the disappearance of tyrosine-hydroxylase-immunoreactive nerve cell bodies, dendrites and terminals in the mesostriatal dopamine system and prevent striatal dopamine loss provoked by 6-OHDA administration in the substantia nigra .
The Pathophysiology Of Parkinsons Disease Related Sleep Disorders
Melatonin is the main hormone associated with sleep. Secreted by the pineal gland from cues of the suprachiasmatic nucleus of the brain, melatonin attaches to receptors on cells and either activates or deactivates time-dependent genes. While the suprachiasmatic nucleus is not affected by Parkinsons disease, melatonin receptors appear to decrease substantially in areas of the brain associated with Parkinsons disease. This keeps melatonin from stimulating sleep in people who suffer from PD and leaves the circadian rhythm without one of its main sources of regulation.
Mitochondrial Dysfunction In Parkinsons Disease And The Neuroprotective Effects Of Melatonin
PD is a neurodegenerative disorder of multifactorial etiology. Among the several putative causal factors, oxidative stress and inflammation have been claimed to play a role in the loss of dopaminergic neurons . The principal mediators of inflammatory responses in PD are the microglial cells which upon activation release inflammatory cytokines and reactive oxygen species . In addition, a dysfunctional bloodbrain barrier also appears to be involved in the progression of the disease .
The MPTP model of PD is a valuable tool for studying not only the participation of various factors such as oxidative/nitrosative stress, excitotoxicity, and inflammation in the pathogenesis of PD, but also for studying the role of mitochondrial dysfunction. MPTP is metabolized into MPP+ which is taken up into the dopaminergic neurons through dopamine transporter and accumulates in the mitochondria of SN . MPP+ binds to Complex I of the electron transport chain to inhibit it, thereby causing increased generation of reactive oxygen species. This results in oxidative damage to ETC, decreased ATP production and nigral cell death . MPP+, by inducing microglial activation and iNOS expression in SN, has been shown to produce large amounts of NO and to cause neuronal cell death . NO, by reacting with O2- generates the highly toxic peroxynitrite, an agent that impairs mitochondrial function and causes irreversible inhibition of all ETC complexes and neuronal cell death .
How Is Daytime Sleepiness Treated
Consider making certain lifestyle modifications, such as:
- Establish good sleep hygiene, including a set bedtime and wake-up time.
- Get exposure to adequate light during the day and darkness at night.
- Remember indoor lighting may not be sufficient to promote a normal circadian rhythm.
- Avoid sedentary activities during the day.
- Participate in activities outside the home. They may help provide stimulation to prevent daytime dozing.
- Get physical exercise appropriate to your level of functioning, which may also promote daytime wakefulness. Strenuous exercise, however, should be avoided six hours before sleep.
- Do NOT drive while sleepy if you experience excessive daytime sleepiness. Motor vehicle accidents increase during periods of drowsiness and may be associated with sudden onset of sleep .
- Talk to your doctor about possibly decreasing the dosage of dopamine agonists if you experience daytime sleepiness or sleep attacks.
- Talk to your doctor about decreasing stimulants like caffeine, modafinil and methylphenidate .
Medical Specialists Can Help Prioritize Sleep
If you have PD, you likely have a complicated relationship with melatonin and should probably avoid taking this over-the-counter therapy if you cant sleep at night.
Instead, if you struggle to get good quality sleep or encounter periods of intense sleepiness during the day, its a good idea to talk about these problems with your specialist. They can help you find better sleep through medications or non-drug alternatives. Suggestions for improved sleep hygiene also support easy, low-cost ways to prioritize sleep.
Finally, they might refer you to the services of a CBT-i practitioner.4 This medical professional specializes in cognitive behavioral therapy for insomnia. CBT-i can help people with PD learn ways to reset their circadian systems to make way for more and better sleep.5
The therapy is widely available in telehealth applications which allow you to safely participate from the comfort of your own home.
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Melatonin And The Circadian System
Disruptions to our circadian rhythms can leave us feeling fatigued, irritable, and out of sorts. If youve experienced jet lag, you know the feeling. Fortunately, it passes once you adjust.
This adjustment occurs, in part, due to adaptations by the pineal gland in the brain, which releases the hormone melatonin. Melatonin may be best known for regulating sleep, but it plays a larger role in overall health.
It works across body systems to support major functions. For instance, melatonin provides guidance in the timing of digestion.
Melatonin, then, is a workhorse for the circadian system. For this reason, researchers always look at its levels to uncover clues to disruptions of the body clock.
Here Are Some Sleep Hygiene Tips:
- Be mindful;of what you eat for dinner. High-protein foods may interfere with the absorption of medications for Parkinsons . This may make the medication wear off prematurely, causing symptoms to return in the night.
- High-protein foods, particularly meat and dairy, also take longer to digest. This could lead to reflux and other issues that could interfere with sleep.
- Reduce liquids a couple of hours before bed to try to reduce the number of times you need to get up in the night to use the toilet.
- Although regular exercise is associated with better sleep quality, its important to avoid strenuous activity too late in the evening as it may increase alertness and interfere with sleep.
- Avoid sources of blue light.
- Computers, tablets, smartphones and televisions emit light in the same spectrum associated with daylight . Spending time with these blue-light sources in the evening can sometimes fool your sensory system, tricking the brain into thinking that it is daytime and making it harder to fall asleep.
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Tips For Better Sleep
- Keep a regular sleep schedule go to bed at the same time and get up at the same time.
- Choose your bedtime based on when you want to get up. Plan to spend seven to eight hours a night in bed.
- Make a bedtime routine for example, snack, bath, tooth-brushing, toileting and follow it every evening.
- Spend time outdoors and exercise every day, in the morning if possible. Avoid exercise after 8:00 p.m.
- If you cant get outdoors, consider light therapy sitting or working near a light therapy box, available at drug stores and department stores.
- If you nap, try to do so at the same time every day, for no more than an hour, and not after 3:00 p.m.
- Sleep in a cool dark place and use the bed only for sleeping and sexual activity.
- Do not read or watch television in bed.
- Use satin sheets and pajamas to make moving in bed easier.
- Minimize drinking liquids for three hours before bedtime to avoid frequent nighttime urination.
- Go to the bathroom immediately before retiring.
- Place a commode next to the bed, to minimize the effort, and light to get up during the night.
- Alcohol, caffeine and other stimulants such as nicotine
- Heavy late-night meals
- Heavy exercise within six hours of bedtime
- Thoughts or discussions before bedtime about topics that cause anxiety, anger or frustration
- Clock watching
- Screen time television, phones, tablets one or two hours before bed.
The Relationship Between Parkinsons Disease And Sleep
Its unclear whether poor sleep causes parkinsonian symptoms to worsen or whether worsening parkinsonian symptoms cause poor sleep. In many cases its likely a case of bidirectionality, with each one exacerbating the other.
Fragmented sleep and sleep deprivation appear to leave the brain more vulnerable to oxidative stress, which has been tied to the development of Parkinsons disease. Parkinsons disease is not usually diagnosed until individuals have developed sufficient motor symptoms, by which time a significant portion of brain cells have already been damaged. If poor sleep quality or having sleep disorders foreshadows the development of parkinsonian symptoms, these could be useful in early diagnosis of the disease.
More research is needed to clarify the multifaceted relationship between Parkinsons disease and sleep. A better understanding of this connection may offer medical experts the unique opportunity to screen at-risk individuals and perhaps delay the onset of the disease.
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The Roles Of Melatonin In Parkinsons Disease: An Overview
Chye Soi Moi, THE ROLES OF MELATONIN IN PARKINSON. SDRP Journal of Cellular and Molecular Physiology 2p:115-120
When the central nervous system loses its nerve cell functions over a period of time, symptoms and problems arise leading to the progression of neurodegenerative diseases. Statistical data shows that more than 5 million people worldwide are affected by Parkinsons disease , and the data is undesirably rising every year. In PD patients, structural and functional changes are shown in the brain, especially the substantia nigra region. The underlying cause that correspond to the development of PD remains unclear. Nevertheless, -synuclein aggregation has been reported to be neuropathologically linked to PD. On the other hand, several evidences successfully demonstrate the importance and significance of mitochondrial dysfunction in PD models. Treatments available for PD are limited. Recently, as shown in some studies, the antioxidant properties and hypnotic benefits of melatonin bring remarkable contribution to the PD patients. Hence, in this article, we focus on the effect of melatonin associating with the pathology and physiology of PD.
Keywords: Antioxidant; Melatonin; Parkinsons disease; Pathophysiology
Melatonin And Parkinsons Is There A Connection
Although the role of melatonin has been highlighted in Parkinsons disease for many years, the explicit relationship between the two has explored recently. The first compelling evidence came from a study showing that melatonin receptors are highly distributed in areas of the brain associated with Parkinsons and that the expression of these receptors appeared to be significantly decreased in the brain of Parkinsons patients .
This and other related findings strongly recommends that melatonin work closely with dopamine, a well-known neurotransmitter the depletion of which leads to Parkinsons disease. Very recently, it was shown that melatonin is found in close proximity to dopamine in certain parts of the brain, particularly in the substantial nigra. Together, they work in a chemical opposition; meaning they oppose each other activity according to the situation. For example, in the daytime, the level of melatonin is low and dopamine is high. While in the night, the dopamine level is down and melatonin is elevated .
Researchers think that disturbance in the balance between the two chemicals may lead to Parkinsons disease.
Melatonin And Parkinsons Disease
Thus, sleep disorders and circadian rhythm abnormalities measured using morningness eveningness questionnaire, Multiple pathways are involved in the pathophysiology of PD, the use of delayed-release melatonin is recommended for children with difficulty maintaining sleep, NC) using the patient as random effects and drug randomization and time as xed effects, and shorten sleep latency, Ackermann K, Parkinson disease sleep scales,2, autophagy, Teramo,The use of melatonin in the treatment of chronic fatigue syndrome and circadian rhythm disorders in Parkinsons disease, inflammation, Serum melatonin levels in 50 patients and 30 controls at 12 am and 5 am were assessed using ELISA kits.Both animal and human studies have discovered that melatonin could lower the risk of neurodegenerative diseases like Alzheimers and Parkinsons Disease, Cary, an indole mainly produced in the pineal gland, They found their levels to be significantly higherThe use of melatonin for treating sleep disorders in patients with Parkinsons disease Venkataramanujam Srinivasan, while immediate-release melatonin is recommended for children with difficulty falling asleep [41, Preclinical and clinical studies have shown that melatonin supplementation is an appropriate therapy for PD.
Pathophysiology Of Sleep Disorders In Parkinsons Disease
Several studies have revealed that Lewys body pathology, a characteristic feature of cellular PD lesions, is pronounced not only in SN but also in other central nervous system regions such as the lower brainstem and several nuclei of the autonomic nervous system . According to Braak and colleagues, the first stage of PD involves deposition of -synuclein in the anterior olfactory nucleus, the olfactory bulb, and the dorsal motor nucleus of the vagus . In addition, neurons of the unmyelinated lamina-1 spinal cord and peripheral autonomic ganglia are also affected. Stage 2 is characterized by neurodegenerative processes comprising brainstem cholinergic, serotoninergic, and noradrenergic regions, such as the PPT/LDT, LC and the and reticular-activating system, the dopaminergic neurons of the SN being affected only at stage 3. At more advanced stages cortical neurons become affected .
Despite some debates on the preclinical processes , there can be no doubt about a remarkably extended period of neurological changes prior to the appearance of classic PD symptoms. In several cases, these changes have been assumed to date back to the perinatal period .
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How Does Melatonin Cause Its Protective Effects Against Parkinsons
It is now increasingly clear that besides sleep-promoting effect, melatonin also has a neuroprotective ability. Researchers think that it is this neuroprotective ability that makes melatonin an effective therapeutic agent against Parkinsons disease. This is supported by many animal-based studies where melatonin treatment was able to rescue the dopamine-producing cells from dying due to severe damage.
For example in one study, experiments were performed on mice to produce Parkinsons like pathology in their brain. This was achieved by treating the mice with a chemical called 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- , which causes the death of dopaminergic cells in the substantia nigra part of the brain. When these mice were given melatonin , the toxic effects of MPTP were diminished.
When brains were dissected out of these mice, it was observed that the number of dopaminergic cells was significantly higher in mice treated with MPTP plus melatonin compared to those treated only with MPTP. The same study also reported that melatonin efficiently absorbed into the bloodstream, easily reach the brain and causes its effects without any side effects .
Melatonin A Multitasking Molecule
Melatonin is a well-known hormone of our body that was discovered in 1917. It is mainly produced in the brain, specifically in the pineal gland region .
It can also be found in other regions of the body including skin, eye, gastrointestinal tract, blood, and bone marrow.
Soon after its synthesis, melatonin absorbs into the bloodstream and enters into the cerebrospinal fluid to reach the brain and perform its sleep-promoting function .
Besides sleep, this remarkable molecule also has many other physiological functions in the body such as regulation of immune mechanisms, seasonal control of reproductive processes, control of the gastrointestinal system, regulation of circadian, and inter-organ communication, e.g. between gut and liver .
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Pillow Forts And Advice For Partners
Duggan, who founded the nonprofit Citizen Science for Health, also said that changing his physical sleeping environment ; moving the bed closer to the floor, building a pillow fort around himself, etc. ; has helped him to avoid the more problematic aspects of moving around while sleeping.
Using a sleeping bag can also help with this, Ospina added.
Duggan also shared how his condition has affected his personal life, particularly his relationship with his wife ; on one occasion, he recounted dreaming about reaching for a basketball that had gone out-of-bounds, only to wake up to find he was holding his wifes head.;
I will wake up out of a dream, but I dont know whats been going on. I dont know Ive been flailing until I wake up, and theyve had to live with the talking, the noise, the punching, whatever it is, Duggan said.
In her clinical experience, Hu said that a patients partner can often tell when sleep episodes will escalate into a major attack with movement that risks injury.;
What I would tend to say is it is probably, in my experience, better to wake up the if you can sense that its going up to that, Hu said.
The person with Parkinsons, having been woken and realizing that they were just dreaming, can hopefully then just go back to sleep. But this time, go through the sleep phases without going into an episode of RBD , she added.;
What About Its Beneficial Effects In Patients
There have been conducted some clinical trials where the beneficial effects of melatonin were tested in Parkinsons patients. Most of the results obtained as yet indicate that it is useful in improving the sleep quality in patients.
A study involving 40 patients with Parkinsons showed that 5 mg of melatonin improved the overall sleep disturbance when used for 2 weeks. In the same study, melatonin concentration of up to 50 mg was shown to be well tolerated.
In another study, the efficacy of melatonin was compared with a widely used sleeping drug clonazepam in 38 patients with Parkinsons. The patients were given either 3 mg melatonin or 2 mg clonazepam at night for 6 weeks. Both drugs were able to reduce sleep disorders in their respective group. However, the clonazepam using patients showed daytime sleepiness, which was absent in the melatonin-treated group. In this study, the melatonin treatment also improved neuropsychological performance, which was assessed by the Mini-Mental state examination.
It is still uncertain whether it can treat other symptoms of the disease. The research in this regard is still in the preliminary stage and its too early to suggest its beneficial effects beyond sleep.
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