Mouse Study Implicates Calcium Channel in Neuronal Death in Parkinson’s Disease

mouse study, Parkinson's

A calcium channel called Cav2.3 plays a role in neuronal death, and may be a useful therapeutic target in Parkinson’s disease, suggests a new study done primarily in mice.

The study, titled “Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease,” was published in Nature Communications.

Motor symptoms in Parkinson’s disease are caused primarily by the death of dopamine-producing (dopaminergic) neurons in a part of the brain called the substantia nigra (SN). It has been well-established that calcium signaling — that is, calcium ions moving in or out (but usually in) of a cell, which is mediated by specialized “channel” proteins — plays an important role in the functioning and survival of these neurons, but the precise mechanisms are still not fully understood.

In the new study, researchers began by measuring the levels of several different calcium channels in these neurons in the brains of mice. They were surprised to find higher levels of Cav2.3 than any other calcium channel; Cav2.3 has never been linked to neurodegeneration (neuron cell death) before.

The researchers then used mice that had been genetically engineered so they could not make Cav2.3 and treated them with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a chemical that is toxic to neurons and is “the standard model for preclinical testing of neuroprotective Parkinson’s disease therapies in animals,” the researchers wrote.

In wild-type (i.e. with functional Cav2.3) mice, MPTP treatment resulted in the death of about 40% of the dopaminergic neurons in the substantia nigra.

“In stark contrast, we observed no loss of SN dopaminergic neurons in Cav2.3 knockout animals after MPTP treatment,” the researchers wrote. “Taken together, these data identify Cav2.3 as mediator of SN dopaminergic neuron vulnerability to a degenerative stressor.”

The researchers then measured levels of other calcium-related proteins in neurons lacking Cav2.3, in order to identify possible mechanisms for this phenomenon. They found that these cells had increased levels (by about 40%) of a calcium-sensing protein called NCS-1, and they hypothesized that higher levels of this protein might lend the neurons protection from MPTP.

To test this, the researchers treated mice that lacked NCS-1 with MPTP, which resulted in the death of about 60% of the dopaminergic neurons in the SN — significantly more than was seen in wild-type mice.

“NCS-1 thus emerges as protective factor during SN dopaminergic degeneration, of likely relevance to Parkinson’s disease,” the researchers wrote.

Finally, the researchers turned to human cells. They took skin cells from volunteers, and engineered these into a type of stem cell called induced pluripotent stem cells (iPSCs), which were subsequently induced to differentiate into neurons.

The researchers compared iPSC-derived neurons from people without Parkinson’s disease to those of a Parkinson’s disease patient who had a mutation in the GBA gene (such mutations are associated with a high risk of Parkinson’s disease).

No significant differences were found in the amount of Cav2.3 protein; however, levels of NCS-1 were about 40% lower in the neurons from the person with Parkinson’s. Although this does not provide definitive proof, it suggests that similar molecular mechanisms might be at play in human Parkinson’s disease.

“Collectively, our data strongly suggest opposing roles for Cav2.3 and NCS-1 in Parkinson’s disease,” the researchers said, adding that “Cav2.3 is neurodegenerative whereas NCS-1 is protective for SN dopaminergic neurons. Whether this involves any direct functional or molecular interactions between the two proteins must be clarified in future experiments.”

“Cav2.3 and NCS-1 thus emerge as potential targets for neuroprotective therapy,” they added.

Although a recent Phase 3 clinical trial (NCT02168842) using DynaCirc (isradipine) — a medicine used to treat high blood pressure — to block another type of calcium channel, called Cav1.3, showed that it did not protect against Parkinson’s disease, the authors believe that the therapeutic dose given may not have been sufficient to fully inihibit this channel in dopaminergic neurons. Alternatively, inhibiting this specific type of calcium channel may “be protective only under distinct conditions, e.g. before motor symptoms manifest, or in response to transiently elevated dopamine levels during dopamine replacement therapy,” they added.

Currently, the only available Cav2.3 inhibitor (SNX-482) is not suitable to be used in a clinical setting “due to off target effects.” As such, the “development of high affinity, brain-permeable, and selective Cav2.3 channel blockers is warranted,” the researchers said.

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#AANAM – Promising Blood Pressure Medicine Fails to Slow Parkinson’s Progression, Trial Results Show

Dynacirc study

In contrast to what was observed in mice, a hypertension medicine called Dynacirc (isradipine) failed to slow Parkinson’s disease progression in humans, according to Phase 3 clinical trial results.

However, “the study did not fail,” according to Tanya Simuni, MD, who presented “A Phase 3 study of isradipine as a disease modifying agent in patients with early Parkinson’s disease (STEADY-PD III): Final study results” during the 2019 American Academy of Neurology Annual Meeting in Philadelphia. Instead, the study’s negative results are important to understand how to fine-tune future approaches for effective treatments, Simuni said.

Belonging to a class of medications called calcium channel blockers, Dynacirc is used to treat high blood pressure (hypertension). The medicine relaxes blood vessels so the heart does not have to pump as hard, ultimately reducing blood pressure. Importantly, Dynacirc can penetrate the central nervous system and reach the brain, where it needs to exert its effects.

A preclinical study demonstrated that upon treatment with Dynacirc dopaminergic neurons — those that are lost as a consequence of Parkinson’s — had levels lower of oxidative stress than those of untreated mice, suggesting the medicine could have a protective role against oxidative stress damage.

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them, resulting in cellular damage as a consequence of high levels of oxidant molecules. Importantly, the molecular phenomenon has been implicated in the degeneration of dopamine-producing neurons.

Researchers believe dynacirc can protect neurons by blocking calcium channels on the surface of dopaminergic nerve cells. Normally these cells are continuously flooded with calcium, fueling cells’ powerhouses (mitochondria), which ends up contributing to harmful oxidative stress and, consequently, nerve cell death.

STEADY‐PD III was a 36-month, Phase 3, placebo‐controlled study (NCT02168842) assessing the effectiveness of Dynacirc 10 mg daily (two daily 5 mg doses) in 336 participants with early Parkinson’s disease who were not receiving dopaminergic therapy.

Participants were assigned randomly to receive Dynacirc or placebo for three years. Subjects had to complete 12 in-person and four telephone visits, during which researchers evaluated patients’ motor, neuropsychiatric, and cognitive skills. Blood and urine samples also were collected.

There were a total of 68 serious adverse events among treatment groups, six of which were deemed possibly related to treatment.

Although considered safe and well-tolerated, the treatment failed to slow progression of Parkinson’s disability. Researchers believe this may have been due to several reasons, including late intervention or inappropriate dosing, as the dose was selected based on tolerability and may not have effectively blocked the desired calcium channels.

Another hypothesis is that this target might not be the leading cause of human Parkinson’s development, or that a single target may not be sufficient to treat or slow disease progression.

“Unfortunately, the people who were taking isradipine did not have any difference in their Parkinson’s symptoms over the three years of the study compared to the people who took a placebo,” Simuni said in a press release. “Of course, this is disappointing news for everyone with Parkinson’s disease and their families, as well as the research community.”

“However, negative results are important because they provide a clear answer, especially for the drug that is commercially available. We will all continue to work to find a treatment that can slow down or even cure this disease,” she added.

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Hypertension Medicine in Phase 3 Parkinson’s Trial Seen to Protect Nerve Cells of Mice from Damage Damage

Dynacirc and Parkinson's

Use of a hypertension treatment called Dynacirc (israpidine) — a calcium channel blocker — eased the type of nerve cell damage seen in Parkinson’s disease, a mouse study reports.

These preclinical findings support an ongoing Phase 3 trial (NCT02168842), known as STEADY-PD III, that is evaluating Dynacirc’s potential to slow Parkinson’s progression in people with early-stage disease.

Findings from the animal study, “Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress,” were published in the Journal of Clinical Investigation.

“Obviously, humans are more complicated than mice, but we’re hopeful the trial will be positive,” D. James Surmeier, PhD, the study’s senior author and a professor at Northwestern University said in a university news article.

Dynacirc is approved to treat high blood pressure, reducing the risk of a heart attack or stroke. Patients taking this medication were seen to have a lower-than-average incidence of Parkinson’s disease, however, intriguing neurologists and neurologic researchers.

They hypothesized that Dynacirc could be exerting a neuroprotective effect on a group of nerve cells called dopaminergic neurons, the death of which is at the core of Parkinson’s motor symptoms.

Dopaminergic neurons are the main source of dopamine in the brain, and are responsible for activities that include mobilizing brain regions to make rapid movement possible.

As such, they have a high energy expenditure, holding their mitochondria — the cell’s power-plants — at full capacity.

“They tune up cellular respiration so that no matter what kind of demand or unexpected excitation comes their way, they can continue to do their job,” Surmeier said.

But a continuous high energy demand has consequences, including the production of toxic compounds that can damage and kill dopaminergic nerve cells, as is the case in Parkinson’s disease.

In blocking calcium channels in a cell, Dynacirc slows cellular mitochondrial activity and thereby reduced the production of damaging byproducts. However, it is still unclear whether the compound can reach the brain and have a direct effect on the mitochondria of neurons.

Researchers treated mice with Dynacirc (given intravenously) for seven to 10 days, successfully blocking calcium channels in dopaminergic neurons and reducing calcium levels inside these cells.

Upon treatment, the mitochondria of dopaminergic neurons showed less oxidant stress than that seen in untreated animals, implying an ability to protect these nerve cells from stress damage.

“We diminished the damage being done to mitochondria enough that dopaminergic neurons looked the same as neurons that are not lost in Parkinson’s disease,” Surmeier said.

No adverse side effects or impact on mice behavior were seen using Dynacirc, the study found, implying safety.

“These data provide additional strong pre-clinical rational for the ongoing Phase 3 study of israpidine [Dynacirc] in human patients,” said Tanya Simuni, MD, lead investigator of STEADY-PD III trial. “We are cautious as so many drugs have failed, but if successful, isradipine will be the first drug to demonstrate the ability to slow progression of Parkinson’s disease.”

The trial, which began in 2014 and is taking place at 54 centers in the United States and Canada, is assessing whether oral  Dynacirc is effective in slowing Parkinson’s progression. About 336 patients with early disease were randomized to receive 5 mg of the treatment or a placebo twice a day for 36 months.

Efficacy will be measured by changes in Unified Parkinson Disease Rating Scale, an assessment of motor and non-motor symptoms, from baseline to study’s end, and changes between treated and placebo study arms. Results are expected in early to mid-2019.

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Source: Parkinson's News Today