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FDA Approves Generic Version of Sinemet for Parkinson’s Treatment, Company Says

Sinemet generic

The U.S. Food and Drug Administration (FDA) has approved a generic equivalent to Sinemet (carbidopa/levodopa) for the treatment of Parkinson’s disease, according to a press release.

The oral therapy, produced by India-based Alembic Pharmaceuticals, will be available as extended-release tablets containing either 50 mg of carbidopa and 200 mg of levodopa, or 25 mg of carbidopa and 100 mg of levodopa.

Sinemet, marketed by Merck, was approved by the FDA in 2014 and is sold as controlled-release tablets in three different strengths: 25 mg of carbidopa and 100 mg of levodopa; 10 mg of carbidopa and 100 mg of levodopa; or 25 mg of carbidopa and 250 mg of levodopa.

People with Parkinson’s have low levels of the neurotransmitter dopamine in the brain. Neurotransmitters are substances produced in response to nerve signals that act as chemical messengers. Direct administration of dopamine cannot be used to increase its levels because it is unable to reach the brain due to the blood-brain barrier, a thin membrane that protects the central nervous system (brain and spinal cord) from the circulatory blood system.

Levodopa and carbidopa act to increase dopamine levels in the brain. Levodopa, a molecule involved in the chemical reaction that produces dopamine, has the ability to cross the blood-brain barrier.

Meanwhile, Carbidopa inhibits enzymes known as decarboxylases that would degrade levodopa, ensuring it reaches the brain. However, carbidopa cannot cross the blood-brain barrier, which allows decarboxylases in the brain to then convert the levodopa to dopamine. Using carbidopa together with levodopa enables the use of lower doses of levodopa, which decreases its side effects, including nausea and vomiting.

The carbidopa and levodopa extended-release tablets also are approved for treatment of postencephalitic parkinsonism, a progressive neurodegenerative disease with clinical features of Parkinson’s, likely caused by an infection, and for people with Parkinson’s symptoms following intoxication by carbon monoxide or manganese.

Brief exposure to air pollution, including to carbon monoxide, has been suggested to increase the risk of Parkinson’s disease and other neurological diseases.

Exposure to the metal manganese may trigger the development of Parkinson’s by promoting the release from nerve cells of the alpha-synuclein protein. The clustering of this protein causes inflammation and neurodegeneration.

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Manganese Exposure May Be Linked to Parkinson’s Development, Study Suggests

manganese

Exposure to the metal manganese may lead to the development of Parkinson’s disease by promoting the release from nerve cells of alpha-synuclein, the subsequent aggregation of which causes inflammation and neurodegeneration, according to a study.

The study, “Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein,” was published in the journal Science Signaling.

Increasing studies have reported that aggregated alpha-synuclein — the main component of Lewy bodies, a Parkinson’s characteristic — is able to migrate within the central nervous system (brain and spinal cord), a process associated with Parkinson’s progression.

Alpha-synuclein induces brain inflammation and neurodegeneration after being secreted from nerve cells in exosomes — tiny vesicles thought to play a role in cell-to-cell transmission of misfolded proteins.

Small amounts of manganese are essential for the proper functioning of certain enzymes in the body. However, exposure to this metal — which has a range of industrial uses as an alloy — in contaminated air and drinking water, as well as in agricultural products, may lead to a movement disorder called manganism with manifestations similar to those of Parkinson’s. Additionally, occupational exposure to manganese in welding fumes has been linked to a higher risk of parkinsonism, a general term for disorders causing movement problems that resemble Parkinson’s.

However, the precise mechanisms through which manganese exerts a neurotoxic effect, as well as its role in alpha-synuclein propagation, are not well-understood by scientists yet.

Researchers at Iowa State University conducted a range of in vitro (in the lab) and in vivo (in animal models) experiments to address this lack of knowledge as well as to evaluate whether exosomes are involved in the transmission of alpha-synuclein.

The in vitro assessments in dopamine-producing nerve cells of mice revealed that exposure to manganese induced the release of misfolded alpha-synuclein through exosomes. These exosomes were then taken up by immune cells called microglia, producing neuroinflammatory responses as reflected by the release of proinflammatory molecules TNF-alpha, interleukin (IL)-12, IL-1beta, and IL-6.

“These results support recent observations indicating that neuroinflammation plays a major role in [Parkinson’s],” the researchers wrote.

In a model of human dopaminergic neurons, exosomes caused toxicity or apoptosis — which refers to “programmed” cell death, as opposed to cell death caused by injury.

A subsequent imaging analysis found that orally delivered manganese accelerated cell-to-cell transmission of aggregated alpha-synuclein, leading to toxicity in dopamine-producing cells. This was assessed in mice injected with a viral vector to produce alpha-synuclein coupled with a fluorescent tag to enable visualization.

Mice that were given both the viral vectors and manganese exhibited more impaired motor function than those injected with the vectors alone, as well as severe loss of dopamine-producing nerve cells in the substantia nigra — an area of the brain known to be affected in Parkinson’s disease.

Researchers also found higher levels of alpha-synuclein in exosomes in blood samples from eight welders, at a mean age of 46 years, with no symptoms of Parkinson’s, compared with 10 healthy individuals used as controls.

“As a group, welders are at risk of prolonged exposures to environmental levels of metals, including [manganese],” the researchers wrote.

The team also observed that injecting alpha-synuclein-containing exosomes collected from cells exposed to manganese into the mouse striatum — a brain region connected to the substantia nigra that also shows lower levels of dopamine in Parkinson’s disease — induced more lethargic behavior as observed by reduced exploratory activity after six months. This was associated with an inflammatory response in the brain.

“Together, these results indicate that [manganese] exposure promotes [alpha-synuclein] secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models,” the researchers wrote.

“As the disease advances, it’s harder to slow it down with treatments,” Anumantha Kanthasamy, PhD, the study’s senior author, said in a press release. “Earlier detection, perhaps by testing for misfolded alpha-synuclein, can lead to better outcomes for patients. Such a test might also indicate whether someone is at risk before the onset of the disease.”

Kanthasamy is the Clarence Hartley Covault distinguished professor in veterinary medicine and the Eugene and Linda Lloyd endowed chair of neurotoxicology at Iowa.

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Mutations in Gene Associated With Hereditary Parkinson’s Disease Lead to Toxic Accumulation of Manganese

SLC30A10 study

Researchers have found that mutations in a gene linked to hereditary forms of Parkinson’s disease — SLC30A10 — cause accumulation of toxic levels of manganese inside cells, which disturbs protein transport and alters nerve cell function, leading to parkinsonian symptoms.

The study “SLC30A10 Mutation Involved in Parkinsonism Results in Manganese Accumulation within Nanovesicles of the Golgi Apparatus” was published in the journal ACS Chemical Neuroscience.

Manganese is an essential metal that helps enzymes carry out their functions in the body. However, too much manganese is toxic, especially for the central nervous system (brain and spinal cord), where its accumulation can lead to parkinsonian-like syndromes.

The SLC30A10 gene encodes an important manganese transport protein, which sits at the membrane of cells and pumps out manganese, to protect cells against this metal’s toxicity. However, mutations in the SLC30A10 gene block the protein’s pumping activity, resulting in manganese accumulation.

Mutations in this gene have been identified as the cause of new forms of hereditary Parkinson’s disease.

“Understanding the means by which mutations in SLC30A10 alter cellular Mn [manganese] homeostasis [manganese equilibrium] is expected to enhance understanding of the principles underlying Mn toxicity itself,” researchers wrote, which may render important information to fight certain forms of familial Parkinson’s disease.

A team of French researchers used advanced imaging techniques to find where manganese accumulates inside cells (cell lines available for laboratory research) carrying disease-causing SLC30A10 mutations versus cells carrying a normal, functional SLC30A10 gene (control cells).

Intracellular manganese levels were undetectable in control cells, confirming cells’ ability to expel the metal and avoid its toxicity. On the contrary, manganese levels were higher in cells carrying disease-causing SLC30A10 mutations.

The team then looked at cells that lacked SLC30A10 and were exposed to increasing levels of manganese. Researchers found that manganese accumulated in an organelle, called the Golgi apparatus, that works as the cell’s dispatching center for proteins. The same was true for cells carrying disease-causing SLC30A10 mutations.

Mutant SLC30A10 proteins lost their ability to expel manganese out of the cells, with cells behaving as if they had no SLC30A10 protein at all.

Using the an imaging technique known as Synchrotron X-ray fluorescence spectrometry, which allows researchers to look deeper into cells and their smaller structures, the team discovered that the main compartment for manganese accumulation in SLC30A10 mutated cells were tiny vesicles released from the Golgi apparatus.

These vesicles are important mediators of communication inside the cell. Researchers believe that disturbing this vesicular trafficking is probably the root of the toxicity induced by the disease-causing mutations of SLC30A10.

“It would be interesting to investigate whether Mn causes defects in Golgi vesicular trafficking and consequently on neurotransmitters,” researchers wrote.

Moreover, these results suggest that small molecules targeting the mutated SLC30A10 protein at the cell surface could become a potential therapeutic strategy.

Future experiments will show if a similar pattern of manganese accumulation is seen in animal models of Parkinson’s disease.

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Nicotine May Protect the Brain from Toxic Trace Metals Linked to Parkinson’s, Cell Study Finds

nicotine study

Nicotine may protect the brain from manganese and iron metal trace elements thought to be involved in the onset of Parkinson’s disease, a study based on a disease cell model reported.

The study, “Nicotine protects against manganese and iron-induced toxicity in SH-SY5Y cells: Implication for Parkinson’s disease,” was published in Neurochemistry International.

Parkinson’s is characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — leading to motor and cognitive impairments.

Although the exact causes of Parkinson’s are not yet fully understood, scientists believe the accumulation of metal trace elements, such as manganese and iron, could play a role in its onset. At low concentrations, these elements are crucial for cell growth and physiological functions; indeed, they are important for all growth and healthy workings of the body. But at high levels, they become toxic, and have been associated with several neurodegenerative disorders, including Parkinson’s.

Nicotine, a potent stimulant originally found in plants that activates the nicotinic acetylcholine receptor (nAChR) in the brain, has been shown to protect dopaminergic neurons from damage caused by different types of toxins. However, no study had addressed possible neuroprotective effects of nicotine against specific metal trace elements.

The new study from Howard University College of Medicine examined the effects of nicotine on toxic manganese and iron elements in a neuroblastoma cell line (SH-SY5Y), a standard in vitro model to study Parkinson’s disease cells, due to their dopaminergic activity.

When researchers exposed SH-SY5Y cells to high concentrations of manganese or iron for a day, toxicity levels increased by 30% and 35%, respectively. Pretreatment with nicotine was seen to completely prevent these toxic effects.

As expected, nicotine’s neuroprotective properties against toxic trace elements were lost when researchers used different types of nicotinic receptor antagonists (molecules that block the activity of nAChRs). This was true for “dihydro-beta erythroidine (DHBE), a selective alpha4-beta2 subtype antagonist and methyllycaconitine (MLA), a selective alpha7 antagonist,” the study noted.  

“In summary, the results of this study provide evidence for neuroprotective effects of nicotine against toxicity induced by Mn [manganese] or Fe [iron] in a cellular model of PD [Parkinson’s disease],” the researchers wrote.

“Moreover, both high and low affinity nicotinic receptors (i.e., alpha4-beta2 and alpha7 subtypes) appear to mediate the effects of nicotine. Thus, utility of nicotine or nicotinic agonists in trace element-induced Parkinson-like syndrome may be suggested,” they concluded.

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