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

 JULY 2, 2018 BY ALICE MELÃO 

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.

https://parkinsonsnewstoday.com/2018/07/02/hypertension-drug-dynacirc-protects-dopaminergic-neurons-in-mice/

The ABCs of Parkinson’s Disease: The Letter C

JULY 2, 2018 BY "SHERRI WOODBRIDGE"

Third in a series. Read part one and two.

In this column, the letter C is for cognitive changes and caregiving.

Cognitive changes

Some possible Parkinson’s disease symptoms are obvious because they are visible: tremors, abnormal gait, a non-swinging arm. You can see them. Others can see them. But some symptoms are not so obvious because they are invisible: internal tremors, dystonia (muscle cramping/twisting), and pain in many and various places.

Other invisible symptoms are cognitive changes (brain symptoms such as disturbance of memory, thinking and language abilities). These changes can range from mild (feelings of distraction or disorganization, finding it difficult to plan and accomplish tasks) to more severe (such as Parkinson’s dementia).

The struggle to remember certain things — such as dates, directions, or where your glasses or car keys are hiding — may be a clue that your cognitive functions are faltering. Or it may be just a case of forgetfulness. It is best to seek out your doctor’s expert advice.

Caregiving

One area that doesn’t get enough attention is caregiving. Sooner or later the Parkinson’s patient will need help, and those tasks will most likely fall upon family members. Whether you are a family member or a good friend, offering your time and extending your love to care for your loved one is a tiring, wearisome task. It takes a lot of energy and time. To prevent burnout, it is important that the caregiver takes time for themselves to keep from becoming resentful and exhausted. Some suggestions include:

• Have lunch with an encouraging friend who knows your situation
• Join a support group for caregivers, a book club, or an exercise or dance class
• Take daily walks
• Listen to encouraging music
• Start a game night with some friends
• Go to church
• Begin a new hobby

The sky’s the limit, but as a caregiver, you are limited in what you can personally give. Try to share the load. Ask a friend if they can sit in for you once in a while when you need to go to the store or grab a hamburger and sit in the parking lot to read a book. You won’t do your “patient” any good if you become resentful for the time it is taking to care for them and lose sight of the fact that they really aren’t trying to make life more difficult for you. It’s just called Parkinson’s disease, and unfortunately, you or your loved one has it. But don’t forget, we’re in this together.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

https://parkinsonsnewstoday.com/2018/07/02/parkinsons-letter-c-cognitive-caregiving/

Compounds found in green tea and wine may block formation of toxic metabolites

July 2, 2018    Tel Aviv University

A new Tel Aviv University study suggests there is hope of treating certain inborn congenital metabolic diseases—a hope found in green tea and in red wine.

Most people with inherited metabolic disorders are born with a defective gene that results in a critical enzyme deficiency. In the absence of a cure, many patients with inborn congenital metabolic disorders must adhere to a strict and demanding diet their entire lives. This new research finds that certain compounds found naturally in green tea and red wine may block the formation of toxic metabolites.

The research was led by Prof. Ehud Gazit of TAU's Faculty of Life Sciences and his doctoral student Shira Shaham-Niv. It was published in the Nature group journal Communications Chemistry.

The researchers considered two compounds: (1) epigallocatechin gallate, known as EGCG, found naturally in green tea, which has attracted attention within the medical community for its potential health benefits; and (2) tannic acid, found in red wine, which is known to prevent the formation of toxic amyloid structures that cause neurodegenerative disorders such as Alzheimer's and Parkinson's disease.

"In the case of inborn congenital metabolic diseases, the body does not produce a vital metabolic enzyme," Shaham-Niv said. "As a result, metabolites—substances that are, among other things, the building blocks of DNA and proteins—accumulate in the body. Such uncontrolled accumulation is toxic and can cause severe developmental and mental disorders.

"Our new study demonstrates once again the ability of nature to produce the best candidate of drugs to treat some of the worst human maladies."

Collectively, this group of disorders constitutes a significant portion of pediatric genetic diseases. The disease phenylketonuria (PKU), which produces the aggregation of the metabolite phenylalanine, is one common inborn metabolic disease. Infants with PKU must adhere to a strict diet free of phenylalanine for the rest of their lives. If they don't, they may face severe debilitating developmental problems.

"But this is an incredibly difficult task, since phenylalanine is found in most of the food products that we consume," Shaham-Niv said. "The avoidance of certain substances is the only way to prevent the debilitating long-term effects of inborn congenital metabolic disorders. We hope that our new approach will facilitate the development of new drugs to treat these disorders."

The new research is based on two previous studies conducted at Prof. Gazit's TAU laboratory. In the first study, phenylalanine was shown to be capable of self-assembly and of forming amyloid structures like those seen in Alzheimer's, Parkinson's and other neurodegenerative diseases. In the second study, by Shaham-Niv, other metabolites that accumulate in other inborn congenital metabolic diseases were also shown to undergo self-assembly processes and form toxic amyloid aggregates.

"Both studies led to an overhaul in the research community's understanding of metabolic diseases," Shaham-Niv said. "In our new study, we examined whether the molecules identified in past studies on Alzheimer's disease and other amyloid diseases, which are known to inhibit the formation of amyloid aggregates, could also help counteract the amyloid formation process of metabolites in metabolic diseases."

The new research focused on EGCG and tannic acid using test tubes and culture cell systems. The two substances were tested on three metabolites related to three innate metabolic diseases: adenine, cumulative tyrosine and phenylalanine. The results were promising. Both tannic acid and EGCG were effective in blocking the formation of toxic amyloid structures. The researchers also used computer simulations to verify the mechanism driving the compounds.

"We are entering a new era of understanding the role and the importance of metabolites in various diseases, including metabolic diseases, neurodegenerative diseases and even cancer," Shaham-Niv concluded. "The tools we have developed are ground-breaking and have tremendous potential to help a wide range of patients in the future."

Provided by: Tel Aviv University

https://medicalxpress.com/news/2018-07-compounds-green-tea-wine-block.html

Experimental drug stops Parkinson's disease progression in mice

 July 2, 2018, Johns Hopkins University School of Medicine

Immunohistochemistry for alpha-synuclein showing positive staining (brown) of an intraneural Lewy-body in the Substantia nigra in Parkinson's disease. Credit: Wikipedia

Johns Hopkins researchers say they have developed an experimental drug, similar to compounds used to treat diabetes, that slows the progression of Parkinson's disease itself—as well as its symptoms—in mice. In experiments performed with cultures of human brain cells and live mouse models, they report the drug blocked the degradation of brain cells that is the hallmark of Parkinson's disease. The drug is expected to move to clinical trials this year.

"It is amazingly protective of target nerve cells," says Ted Dawson, M.D., Ph.D., director of the Institute for Cell Engineering and professor of neurology at the Johns Hopkins University School of Medicine.

Dawson explains that if planned clinical trials for the drug, named NLY01, are successful in humans, it could be one of the first treatments to directly target the progression of Parkinson's disease, not just the muscle rigidity, spasmodic movements, fatigue, dizziness, dementia and other symptoms of the disorder.

NLY01 has been called 'amazingly protective' as preliminary trials by Johns Hopkins University researchers showed it blocked brain cells from dying (stock)

A report of the study's results was published June 11 in Nature Medicine.

According to the investigators, NLY01 works by binding to so-called glucagon-like peptide-1 receptors on the surface of certain cells. Similar drugs are used widely in the treatment of type 2 diabetes to increase insulin levels in the blood. Though past studies in animals suggested the neuroprotective potential of this class of drugs, researchers had not shown directly how it operated in the brain.

To find out, Dawson and his team tested NLY01 on three major cell types in the human brain: astrocytes, microglia and neurons. They found that microglia, a brain cell type that sends signals throughout the central nervous system in response to infection or injury, had the most sites for NLY01 to bind to—two times higher than the other cell types, and 10 times higher in humans with Parkinson's disease compared to humans without the disease.

Dawson and his team knew that microglia secreted chemical signals that converted astrocytes—the star shaped cells that help neurons communicate with their neighbors—into aggressive "activated" astrocytes, which eat away at the connections between cells in the brain, causing neurons to die off. They speculated that NLY01 might stop this conversion.

"The activated astrocytes we focused on go into a revolt against the brain," says Dawson, "and this structural breakdown contributes to the dead zones of brain tissue found in those with Parkinson's disease. The ideas was that if we could find a way to calm those astrocytes, we might be able to slow the progression of Parkinson's disease."

In a preliminary experiment in laboratory-grown human brain cells, Dawson's team treated human microglia with NLY01 and found that they were able to turn the activating signals off. When healthy astrocytes were combined with the treated microglia, they did not convert into destructive activated astrocytes and remained healthy neuroprotective cells. Dawson's team suspected that neurons throughout the body could be protected in the same way.

They explored this hypothesis by testing the drug's effectiveness in mice engineered to have a rodent version of Parkinson's disease.

In one experiment, Dawson's team injected the mice with alpha-synuclein, the protein known to be the primary driver of Parkinson's disease, and treatedmice with NLY01. Similar but untreated mice injected with alpha-synuclein showed pronounced motor impairment over the course of six months in behavioral tests such as the pole test, which allows researchers to measure motor impairment such as that caused by Parkinson's disease. However, Dawson's team found that the mice treated with NLY01 maintained normal physical function and had no loss of dopamine neurons, indicating that the drug protected against the development of Parkinson's disease.

In a second experiment, Dawson's team used mice that were genetically engineered to naturally produce more human-type alpha-synuclein typically used to model human Parkinson's disease that runs in families. Under normal conditions, these so-called transgenic mice will succumb to the disease in 387 days. However, Dawson's team found that treatment with NLY01 extended the lives of the 20 mice treated with the drug by over 120 days.

Upon further investigation, Dawson's team found that the brains of the mice treated with NLY01 showed few signs of the neurodegenerative characteristics of Parkinson's disease.

Parkinson's disease is a progressive disorder of the nervous system that affects approximately 1 million people in the U.S., according to the Parkinson's Foundation. Early symptoms include tremors, trouble sleeping, constipation and trouble moving or walking, which ultimately give way to more severe symptoms such as loss of motor function and the ability to speak, and dementia. Most people begin showing symptoms in their 60s, but cases have been reported in patients as young as 2 years old.

Dawson cautions that the experimental drug must still be tested for safety as well as effectiveness in people, but based on the safety profile of other similar drugs, he does not anticipate any major roadblocks to its use in humans.

Dawson says he and his team have reason to be hopeful that NLY01 could, in a relatively short period of time, make an impact on the lives of those with Parkinson's.

Similar drugs to NLY01 already approved by the Food and Drug Administration for the treatment of type 2 diabetes include exenatide, lixisenatide, liraglutide and dulaglutide, each of which can cost approximately $2,000 for a 90-day supply. NLY01 is a long-acting drug with improved the brain penetration compared to these approved drugs for diabetes.

More information: Seung Pil Yun et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease, Nature Medicine(2018). DOI: 10.1038/s41591-018-0051-5

Journal reference: Nature Medicine

Provided by: Johns Hopkins University School of Medicine 

https://medicalxpress.com/news/2018-07-experimental-drug-parkinson-disease-mice.html

FoxFeed Blog: Takeaways from Talking to 50 Parkinson's Experts

Posted by Maggie McGuire Kuhl,   June 29, 2018

Benjamin Stecher is taking an investigative approach to his own Parkinson's diagnosis. He writes in a new blog post on the Journal of Parkinson's Disease website:

For the past six months, I have been recording and transcribing interviews with a wide variety of Parkinson's specialists and biomedical researchers. It has been an incredibly enlightening experience that has given me insights into my own journey with Parkinson's disease, as well as the future of biomedical science ...

We are living through an explosion in our understanding of the brain and its associated biology. Entire fields of research have popped up in the last few decades that would have been solely the domain of science fiction a mere generation ago. Optogenetics, neuromodulation, iPS cell therapy, neuroimmunology, gene therapy, brain organoids, etc., etc. Each has brought with it some profound new insights into how we work and what goes wrong as we age. They have also given us reason to believe that one day we will be able to properly treat this and other diseases.

Stecher lists takeaways from his interviews with experts, including many Michael J. Fox Foundation (MJFF) advisors and grantees.

MJFF CEO Todd Sherer, PhD, commented on the shift to understand and treat Parkinson's more by its biology than its clinical symptoms, which could help develop and test precision medicine approaches.

"We need to move this beyond phenomenology [looking at experience] and into understanding by identifying biological subgroups of the disease and then develop very specific biological targets against that subgroup," he said.

https://www.michaeljfox.org/foundation/news-detail.php?takeaways-from-talking-to-50-parkinson-experts

Read the full post and comments from other Parkinson's scientists:

https://www.journalofparkinsonsdisease.com/blog/stecher/putting-it-all-together-reflections-fifty-interviews-world-leading-parkinson’s-and

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https://www.michaeljfox.org/foundation/news-detail.php?takeaways-from-talking-to-50-parkinson-experts

Voyager's Parkinson's Gene Therapy Is Likely To Fail

July 1, 2018    About: Voyager Therapeutics (VYGR)   By John Kastanes

Summary

Initial phase 1 Parkinson's gene therapy results were similar to placebo in other Parkinson's surgeries.

Sanofi reviewed the Parkinson's gene therapy clinical data and walked away.

Voyager needs to raises money; it will most likely be an equity offering before phase 1b and phase 1 posterior trajectory data is released.

Voyager Therapeutics (VYGR) is a clinical-stage gene therapy company focused on developing treatments for patients suffering from severe neurological diseases using an adeno-associated virus, or AAV, gene therapy approach, that either increases or decreases the production of a specific protein.

(source: 2017 annual report)

Voyager's pipeline consists of six programs for severe neurological indications, including advanced Parkinson’s disease; a monogenic form of amyotrophic lateral sclerosis, or ALS; Huntington’s disease; Friedreich’s ataxia; tau-related diseases including Alzheimer’s disease, frontotemporal dementia, and progressive supranuclear palsy; and severe, chronic pain.

Given VY-AADC in the only gene therapy in clinical trials, this article will focus on the consequences of success or failure of VY-AADC.

Financials

From Voyager's Q1 2018 earning report

As of March 31, 2018 cash, cash equivalents, and marketable debt securities were $218.2 million. Based on the current operating plan, Voyager continues to expect to end 2018 with total cash, cash equivalents and marketable debt securities of approximately $125 million to $135 million and projects that its existing cash, cash equivalents and marketable debt securities will be sufficient to fund operating expenses and capital expenditure requirements through 2019.

VY-AADC clinical trials and results

Initial phase 1A phase 1 clinical trial conducted at University of California San Francisco, or UCSF, in a total of 10 patients with advanced Parkinson's. Two does of VY-AADC were tested. The primary endpoints of this trial were safety and tolerability. These endpoints were met with no treatment related severe adverse events, or SAEs.

The 10 patients were assessed clinically for up to four years after treatment and a durable, dose-dependent expression of AADC was observed. Patients treated with the low dose gene therapy were observed to have an increased PET signal indicative of AADC expression and activity that persisted for up to four years. Patients treated with the high dose gene therapy were observed to have an increased PET signal that was greater on average when compared to the low dose cohort, which also persisted for up to four years.

A similar phase 1 clinical trial was conducted at Jichi Medical University, or JMU, in Japan using the same vector that was used in the UCSF trial. Six patients were treated in this trial and an enhanced PET signal was observed in a subset of patients monitored 96 weeks following treatment. Patients remain in follow up in an open-label Phase 1/2 trial currently being conducted at JMU.

Phase 1b

In 2014, UCSF initiated an open-label phase 1b clinical trial to optimize the development of VY-AADC. The primary endpoints of this trial were safety and tolerability. Secondary endpoints of this trial, which are being used to assess the potential pharmacologic activity of VY-AADC, include Unified Parkinson's Disease Rating Scale, or UPDRS, AADC PET imaging and a behavioral test using intravenous levodopa treatment to measure changes in a patients’ sensitivity to levodopa as well as endpoints to measure motor functions.

Phase 1 posterior trajectory

During 2017, Voyager dosed seven patients in a phase 1 trial designed to optimize the intracranial delivery of VY-AADC. This phase 1 trial was designed to explore using a posterior delivery approach of drug into the putamen, compared to a transfrontal delivery approach used in Cohorts 1 through 3 of the ongoing phase 1b study. A posterior approach better aligns the infusion of VY-AADC with the anatomical structure of the putamen to potentially reduce the total procedure time and increase the total coverage of the putamen.

Posterior trajectory (source: 2017 annual report)

 

Voyager expects to provide longer-term safety data from the phase 1b and phase 1 posterior trajectory trials during the second half of 2018.

Planned pivotal phases 2 and 3

Voyager plans to dose the first patient in the global pivotal phase 2 in mid-2018. Based on estimates of patient enrollment and a 12-month blinded treatment period, Voyager expects top-line data from the phase 2 study in the second half of 2020. Voyager anticipates enrollment in the phase 3 trial will begin during the first half of 2019. Based on estimates of patient enrollment and a 12-month blinded treatment period, Voyager anticipate top-line data from the phase 3 trial during the first half of 2022.

What investors need to know

Voyager's 2017 annual report mentioned the following in regards to the initial phase 1 conducted by UCSF and phase 1b

The magnitude of the clinical responses seen in the phase 1 clinical trial of AAV2-AADC conducted by UCSF were similar to placebo effects observed in previous surgical therapies for Parkinson’s disease.

In February 2015, Voyager entered into a strategic collaboration with Sanofi (SNY) to develop AAV gene therapies for certain severe neurological diseases including ex-U.S. rights to VY-AADC. Under the agreement, Voyager received $65.0 million in upfront cash, a $30.0 million upfront equity investment, and an in-kind commitment of $5.0 million, totaling $100.0 million. At the inception of the agreement, Voyager was eligible to receive up to $745.0 million in option and milestone payments.

In October 2017, Sanofi notified Voyager that it had decided not to exercise its option for the ex-U.S. rights to VY-AADC.

On June 28th, Voyager appointed G. Andre Turenne as its new President and CEO, as well as a director. Previous CEO Dr. Steven Paul will continue to serve on Voyager’s Board of Directors and as a member of Voyager’s Science & Technology Committee.

Oxford BioMedica (OTCPK:OXBDF) developed a similar gene therapy for Parkinson's OXB-101, or ProSavin, that delivers three genes encoding a set of enzymes required for dopamine synthesis in the brain. 

Oxford completed a Phase 1/2 study for OXB-101, which met its primary end-point, according to the company. The results, published in The Lancet stated:

ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients.

However, according to Raymond Bartus, PhD chief science officer at Ceregene, Inc. (a non-public company) who led an experimental gene therapy for Parkinson's stated:

the modest efficacy improvements reported in The Lancet paper also are comparable to those reported in many, prior gene therapy Parkinson's studies; importantly, studies of those treatments could not adequately differentiate between treatment and placebo.

Oxford designed a second-generation Parkinson's gene therapy, OXB-102, and licensed it and OXB-101 to Axovant Sciences (AXON).

Conclusion 

Patients in the initial phase 1 trial were observed to have an increased PET signal indicative of AADC expression and the activity persisted for up to four years, yet results were similar to placebo effects observed in other Parkinson's surgeries.

Sanofi reviewed VY-AADC clinical data and walked away.

Voyager has enough money to operate through 2019. With top-line phase 2 data not anticipated until late 2020, Voyager has to raise money. I expect Voyager to announce an equity offering before phase 1b and phase 1 posterior trajectory data is released later this year, further diluting shareholders.

If you are contemplating investing in Voyager, I recommend waiting for phase 1b and phase 1 posterior trajectory data. If data is less than compelling, shares could see a significant price drop. If you are a shareholder, I recommend exiting your position.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Editor's Note: This article discusses one or more securities that do not trade on a major U.S. exchange. Please be aware of the risks associated with these stocks.

https://seekingalpha.com/article/4184952-voyagers-parkinsons-gene-therapy-likely-fail

Arvid Carlsson, Who Discovered a Treatment for Parkinson’s, Dies at 95

 July 1, 2018

Dr. Arvid Carlsson and his wife, Ula, after learning he would receive the 2000 Nobel Prize in Physiology or Medicine. He shared the award with two American scientists, Paul Greengard and Eric Kandel.Reuters

Dr. Arvid Carlsson, a Swedish scientist whose discoveries about the brain led to the development of drugs for Parkinson’s disease and earned him a Nobel Prize, died on Friday. He was 95.

His death was announced by the Sahlgrenska Academy at the University of Gothenburg, where he had been a professor of pharmacology. It did not say where he died.

When Dr. Carlsson started his research in the 1950s, dopamine, a chemical in the brain, was thought to have little significance. Dr. Carlsson discovered that it was, in fact, an important neurotransmitter — a brain chemical that passes signals from one neuron to the next.

He then found that dopamine was concentrated in the basil ganglia, the portion of the brain that controls movement. He showed that rabbits lost their ability to move after they were given a drug that lowered their dopamine stores; their mobility was restored after they received L-dopa, a drug that is converted into dopamine in the brain.

Noting that the movement difficulties of his rabbits were similar to those of people with Parkinson’s disease, Dr. Carlsson proposed that the illness was related to a loss of dopamine. Other scientists confirmed that dopamine is depleted in people with Parkinson’s disease, a degenerative condition that causes tremors and rigidity, and L-dopa soon became the standard treatment for the illness.

Dr. Carlsson shared the 2000 Nobel Prize in Physiology or Medicine with two American researchers, Dr. Eric Kandel and Paul Greengard, who made their own discoveries about the transmission of chemical signals in the brain. In awarding the Nobel, the Karolinska Institute of Sweden said the contributions of the three scientists were “crucial for an understanding of the normal function of the brain” and for how signal disturbances could “give rise to neurological and psychiatric disorders.”

Arvid Carlsson was born on Jan. 25, 1923, in Uppsala, Sweden, one of four siblings in “an academic middle-class family,” he wrote in an autobiographical sketch for the Nobel committee. He grew up in the Swedish city of Lund, where his family moved after his father joined the University of Lund faculty as a history professor.

“My mother had passed a master-of-arts examination and my father a Ph.D. degree at the University of Uppsala,” Dr. Carlsson wrote. “My mother had a keen interest in research throughout her life but gave priority to raising her children and to assisting her husband in his research. However, when her husband died at the age of 76 she, then 71 years old, started to devote herself entirely to her favorite area of research, that is the legal status of women in the Middle Ages in Sweden. She published a couple of books and a number of articles on this subject in Swedish, which rendered her an honorary Ph.D. degree at the University of Uppsala several years later.”

His family had a “strong orientation toward the humanities,” Dr. Carlsson wrote. His older brother and sister followed his father into the humanities, but Dr. Carlsson, in an act of youthful rebellion, chose to study medicine, a field he saw as more useful than the arts.

During World War II, Dr. Carlsson, who had hitchhiked to Germany with a friend as a teenager in the summer of 1939, before the outbreak of World War II, was in his first year of clinical training when, in 1944, he was recruited to examine former prisoners of German concentration camps, many of them Jews, who had been transported by the thousands to Sweden through the efforts of the Swedish royal family.

“Some of the prisoners were taken to Lund, where a big tent was erected in a park to house them,” he wrote. “As a medical student I was given the task to examine several of these prisoners. Many of them were children, suffering from undernutrition. Tuberculosis was not uncommon. However, most shocking was their mental status. They behaved like wild animals, obviously suffering from severe anguish and suspiciousness and trusting nobody.”

Dr. Carlsson in 1969.Fls/Associated Press

Dr. Carlsson received his medical degree and his doctorate in pharmacology in 1951 from the University of Lund and joined the faculty as an associate professor. After several years he applied for an assistant professorship but was turned down; a review committee told him that his specialty, calcium metabolism, wasn’t leading edge.

“I realized I had to make a choice to either leave pharmacology and go into internal medicine, or switch into a new research field,” he wrote. His search for a new specialty led him to the United States and a five-month fellowship with Bernard B. Brodie, an acclaimed pharmacologist at the National Heart Institute (now the National Heart, Lung and Blood Institute in Bethesda, Md.). His brief stint in the Brodie lab reinvigorated Dr. Carlsson’s career, and set him on the path to his Nobel Prize.

Dr. Brodie had been studying reserpine, one of the first drugs introduced specifically to treat schizophrenia, which made it a hot subject for research. Reserpine injections immobilized rabbits, but no one understood why. Shortly before Dr. Carlsson’s arrival, Dr. Brodie determined that reserpine depleted serotonin, a neurotransmitter that would later be associated with mood and depression. Assigned to study the effect of reserpine on serotonin in blood cells, Dr. Carlsson immersed himself in the emerging field of psychopharmacology.

“I can hardly overemphasize enough how lucky I was to get that opportunity to work in Dr. Brodie’s laboratory,” Dr. Carlsson wrote.

When his fellowship ended in mid-1956, Dr. Carlsson returned to the University of Lund as an associate professor and continued to study reserpine. Building on Dr. Brodie’s research, he found that the drug depleted a second neurotransmitter, noradrenaline. This discovery presented a conundrum: Was it serotonin or noradrenaline that controlled movement?

The rabbits did not improve when given a drug that spurs production of serotonin. When the animals improved on L-dopa, Dr. Carlsson thought he had solved the puzzle. Noradrenaline is synthesized in the body from dopamine, which in turn is metabolized from L-dopa. But Dr. Carlsson was in for a surprise. When he examined the brains of the revived animals, he found very little noradrenaline and plenty of dopamine.

Up to this point, scientists thought dopamine was nothing more than raw material for making noradrenaline. Dr. Carlsson discovered that dopamine was a neurotransmitter in its own right — one with a critical role in movement.

All Parkinson’s disease drugs used today work by increasing dopamine signaling in the brain. More than 50 years after Dr. Carlsson’s discovery, L-dopa remains the mainstay treatment.

In the 1960s, Dr. Carlsson showed that antipsychotic drugs work by blocking receptors on neurons that receive dopamine signals. He was among the first to determine that some addictive drugs, such as cocaine, increase dopamine signaling in certain parts of the brain. Later, he made important contributions that led to the development of selective serotonin reuptake inhibitors, or SSRIs, a class of antidepressants that includes Prozac.

He became a professor at the University of Gothenburg in Sweden in 1959 and a professor emeritus in 1989. He was admitted to the Royal Swedish Academy of Science in 1975 and received the Japan Prize in 1994.

He and his wife, Ulla Lisa, had three sons and two daughters. A list of survivors was not immediately available.

In his later years, Dr. Carlsson was an outspoken critic of fluoridating water supplies to prevent cavities. He said that fluoride produces side effects, such as mottled teeth, and that fluoridation was contrary to the principles of modern pharmacology because there was no way to regulate the amount of fluoride individuals received. He argued that individualized preventive care was a better approach.

https://www.nytimes.com/2018/07/01/obituaries/arvid-carlsson-who-discovered-a-treatment-for-parkinsons-dies-at-95.html