Abstract
Millions of individuals around the world are afflicted with Parkinson’s disease (PD), a prevalent and incapacitating neurodegenerative disorder. Dr. Reichmann, a distinguished professor and neurologist, has made substantial advancements in the domain of PD research, encompassing both fundamental scientific investigations and practical applications. His research has illuminated the etiology and treatment of PD, as well as the function of energy metabolism and premotor symptoms. As a precursor to a number of neurotransmitters and neuromodulators that are implicated in the pathophysiology of PD, he has also investigated the application of tryptophan (Trp) derivatives in the disease. His principal findings and insights are summarized and synthesized in this narrative review article, which also emphasizes the challenges and implications for future PD research. This narrative review aims to identify and analyze the key contributions of Reichmann to the field of PD research, with the ultimate goal of informing future research directions in the domain. By examining Reichmann’s work, the study seeks to provide a comprehensive understanding of his major contributions and how they can be applied to advance the diagnosis and treatment of PD. This paper also explores the potential intersection of Reichmann’s findings with emerging avenues, such as the investigation of Trp and its metabolites, particularly kynurenines, which could lead to new insights and potential therapeutic strategies for managing neurodegenerative disorders like PD.
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Introduction
Parkinson’s disease (PD) is a long-term degenerative disorder characterized by a gradual decline in the number of neurons in the brain that produce dopamine (Kordower et al. 2013; Triarhou 2013; Meder et al. 2019). Dopamine plays a vital role in controlling movement, and a lack of it results in the distinct motor symptoms associated with PD, including tremors, rigidity, bradykinesia, and compromised balance and coordination (Kumar et al. 2022b; Mazzoni et al. 2012; Moustafa et al. 2016). In addition, PD can also affect non-motor functions, including mood, cognition, and sleep patterns (Poewe 2008; Burn et al. 2012; Herman et al. 2015; Maass and Reichmann 2013). While the exact etiology of PD remains uncertain, it is widely accepted that a combination of genetic and environmental factors plays a role in its pathogenesis (Tsuboi 2012; Polito et al. 2016; Fleming 2017). At present, there is no known remedy for PD; however, a range of medications and therapies exist to effectively alleviate symptoms and improve the overall well-being of individuals affected by this condition (Dong et al. 2016; Yuan et al. 2010; Kwok et al. 2016). Continuing research and progress in comprehending the disease provide optimism for potential future treatment alternatives and interventions (Valotto Neto et al. 2024; de Oliveira Zanuso et al. 2022; Buglio et al. 2022; Barbalho et al. 2022; Matias et al. 2021; Pagotto et al. 2024).
Prior to James Parkinson’s publication of his essay on shaking palsy in 1817, PD had been recognized and recorded by different cultures and medical professionals (Blonder 2018; Lees 2007). Ancient India referred to it as Kampavata and treated it with plants containing levodopa, a dopamine precursor (Ovallath and Deepa 2013; Bhattacharyya 2022). Mucuna pruiens, a tropical leguminous plant, has been used in Ayurvedic medicine for centuries (Verma et al. 2014). L-dopa accounts for approximately 5% of the phenolic compounds found in Mucuna seed velvet bean (Vadivel and Pugalenthi 2008; Foley 2003). In ancient Greece and Rome, Galen described it as shaking palsy and differentiated between resting and action tremors (Molina-Negro and Hardy 1975; Lanska 2009; Blattspieler 1946). In the 17th and 18th centuries, several European authors, such as Pápai Páriz, Sagar, Gaubius, Hunter, and Chomel, reported cases of PD and suggested various therapies (Blattspieler 1946; García Ruiz 2004; Arredondo-Blanco et al. 2018). However, it was James Parkinson who first identified PD as a distinct neurological disorder and provided a detailed description of its symptoms, in “An Essay on the Shaking Palsy” (Fig. 1) (Parkinson 1817, 2002; McDonald et al. 2018; Halliday et al. 2011).
James Parkinson, an English physician, was the first to characterize PD in 1817, identifying symptoms like tremor, rigidity, and bradykinesia (Parkinson 1817, 2002; Schiller 1986; Bhattacharyya 2017). He named it paralysis agitans and suggested treatments like opium and bloodletting (Parkinson 2002). Jean-Martin Charcot, a French neurologist, improved the diagnosis of PD and named it after Parkinson (Charcot 1877; Lees 2007). He together with Leopold Ordenstein and then Wilhelm Erb utilized anticholinergic medications hyoscyamine and scopolamine, respectively to address certain symptoms (Goetz 2011; Schulz et al. 2011; Foley 2003). Arvid Carlsson, a Swedish pharmacologist, found that reserpinized hares’ brains with dopamine deficits exhibited PD-like symptoms. The conditions were alleviated by DL-dopa (Carlsson et al. 1957, 1958; Carlsson 1964). He used levodopa, the initial successful treatment for the condition, earning him the Nobel Prize in 2000 (Carlsson et al. 1957; Birkmayer and Hornykiewicz 1961; Carlsson 2001). George C. Cotzias, a Greek-American neurologist, was a trailblazer in utilizing high doses of levodopa and researching its impacts and adverse reactions (Cotzias et al. 1967, 1969; Cotzias 1971). Meanwhile, seminal clinical studies revealed that combining levodopa with the dopa decarboxylase inhibitor (DDI) had a levodopa-saving effect. The combination of levodopa and DDI has now become the gold standard for treating PD (Birkmayer and Mentasti 1967; Keller et al. 2011). Cotzias also experimented with other medications, such as dopamine receptor agonist apomorphine, for PD (Cotzias et al. 1970). Anders Björklund, a prominent Swedish neuroscientist, is a pioneer in the area of neural transplantation for PD. He and his colleagues implant fetal dopamine neurons into the brains of PD patients to enhance their symptoms and analyze their survival and incorporation (Lindvall et al. 1990). However, adverse reactions, including graft-induced dyskinesias, were observed, necessitating the withdrawal of this strategy and its ongoing investigation (Bjorklund and Kordower 2013). These individuals are prominent in the field of PD, but there are numerous others who have contributed significantly to the understanding and management of this condition. Ongoing research is being conducted on PD, with the development of new therapies aimed at improving the quality of life for individuals affected by the condition (Fig. 1).
A German neurologist Dr. Reichmann has made substantial contributions to the field of PD research, which is essential for enhancing our comprehension of this intricate neurodegenerative condition (Klingelhoefer and Reichmann 2017). His innovative research has provided valuable insights into different facets of the illness, such as its causes, development, and possible points of intervention for treatment (Reichmann 2011; Klingelhoefer and Reichmann 2015; Ossig and Reichmann 2013). His research has contributed to better understand alpha-synuclein (α-syn) protein aggregation in the development of PD, contributing to the understanding of the processes that lead to the degeneration of dopaminergic neurons (Riederer et al. 2019; Becker et al. 1995; Pan-Montojo et al. 2012). Moreover, investigations into the genetic and environmental factors linked to the disease have yielded valuable insights into its multifactorial nature (Klingelhoefer and Reichmann 2017; Balbona et al. 2022; Kidd 2000). By understanding his contributions to PD research, we can enhance our understanding of the disease and facilitate the progress of developing efficacious treatments, which could potentially enhance the quality of life for millions of individuals afflicted by this incapacitating condition.
Although Reichmann and other researchers have made significant research efforts, there is still a lack of knowledge in the field of PD that requires additional investigation. PD, a multifaceted neurological disorder, has been subject to thorough investigation over time, resulting in substantial advancements in our understanding of its etiology, manifestations, and progression (Kouli et al. 2018; Rodriguez-Oroz et al. 2009; Poewe and Mahlknecht 2009). Nevertheless, the specific mechanisms responsible for its onset and progression remain unclear. Although there are many treatments that show promise in managing symptoms, there is a need for the development of more effective and targeted therapies to slow or halt disease progression (Oertel and Schulz 2016; Ntetsika et al. 2021; Sardi et al. 2018). Continuing research is crucial to unravel the complexities of this condition and discover new therapeutic targets and personalized interventions for patients, ultimately improving their quality of life.
Reichmann’s invaluable contributions to research on PD have greatly enhanced our comprehension of this intricate neurodegenerative disorder. PD has been linked to oxidative stress, reduced antioxidant capacity, excitotoxicity, mitochondrial dysfunction, proteasomal dysfunction, apoptosis, lysosomal dysfunction, and impaired autophagy. These factors contribute to α-synuclein fibril formation, neuroinflammation, and cell death. Understanding these mechanisms can inform the development of targeted therapies to slow or prevent disease progression (Cohen 1983; Heikkila et al. 1984; Riederer et al. 2021). His groundbreaking research on the impact of oxidative stress in PD has uncovered the harmful consequences of free radicals on dopaminergic neurons, suggesting that oxidative stress could be a viable target for therapy (Reichmann et al. 2012b; Gille et al. 2004; Dexter and Jenner 2013; Jászberényi et al. 2024). Furthermore, his investigation into inflammation and specifically, neuroinflammation has yielded vital understandings regarding the progression of diseases and possible approaches to intervention (Holzer et al. 2017; Reichmann et al. 2002; Nagatsu and Sawada 2005; Nagatsu et al. 2000). His work not only enhanced our comprehension of PD but also expanded the potential for future investigation. Given these discoveries, upcoming research should focus on investigating innovative therapeutic approaches that specifically address oxidative stress and inflammation (Pajares et al. 2020; Colombo et al. 2020; Jiang et al. 2016; Tanaka and Vécsei 2021; Fornari Laurindo et al. 2023; de Souza et al. 2020). Additionally, it is important to explore potential biomarkers that can be used for the early detection and continuous monitoring of disease advancement (Berg 2008; Molochnikov et al. 2012; Lotankar et al. 2017; Tanaka and Vécsei 2020; Höglinger et al. 2024; Höglinger and Lang 2024). In order to make progress in the field, potential areas for future research could include studying the molecular pathways involved in the development of PD, identifying early biomarkers for accurate diagnosis, and developing targeted interventions to slow down or stop the progression of the disease (Tanaka et al. 2023b Török et al. 2020).
Moreover, Reichmann’s research has made a substantial contribution to presenting potential strategies for improved diagnosis and treatment. The outcomes of his research have facilitated the development of improved diagnostic methods, enabling the earlier and more precise identification of PD (Bhidayasiri and Reichmann 2013; Ossig and Reichmann 2015a). Timely diagnosis enables the implementation of suitable treatments and interventions to effectively control symptoms and decelerate the progression of the disease (Pahwa and Lyons 2010; Bloem et al. 2019). Furthermore, his research has also investigated novel therapeutic methods, such as neuroprotective strategies and deep brain stimulation, that show potential for enhancing the quality of life for individuals with PD (Polanski et al. 2010; Keller et al. 2020; Sarkar et al. 2016; McKinnon et al. 2019; Tanaka and Vécsei 2021). Thus, Reichmann’s impact on PD research is multifaceted and far-reaching. This narrative review article aims to provide a short but clear overview of his significant contributions. By highlighting key areas such as motor and non-motor symptoms, health-related quality of life, energy metabolism, and etiopathogenesis, readers gain insight into the breadth of Reichmann’s work. Additionally, this review attempts to identify research gaps and sets the stage for discussing potential future avenues. These avenues may include novel biomarkers, innovative therapies, and personalized medicine approaches. Ultimately, the article underscores the patient-centric goal: improving diagnosis and treatment outcomes for those affected by this debilitating condition.
The progress in understanding the etiology and management of Parkinson’s disease
Prior to the pioneering research conducted by Reichmann, PD was primarily recognized as a neurodegenerative disorder characterized by the loss of dopamine-producing neurons in the brain, resulting in classical Parkinsonian motor symptoms such as tremors, rigidity, and bradykinesia (Goetz 2011; Reichmann and Jost 2023a). The etiology of the disease is associated with a complex interplay of genetic and environmental factors (Pang et al. 2019; Allam et al. 2005; Bogers et al. 2023). Traditional treatment strategies have focused on alleviating symptoms through dopamine replacement therapy, including levodopa, and other medications that target motor impairments as well as non-motor symptoms, such as depression and sleep disturbances.
Dr. Reichmann’s contributions to Parkinson’s disease research and treatment
Reichmann’s extensive research on energy metabolism, premotor symptoms, and the etiopathogenesis and treatment of PD has significantly advanced our understanding of this condition (Reichmann and Janetzky 2000; Reichmann 2016, 2017; Klingelhoefer and Reichmann 2015; Storch et al. 2013). His groundbreaking contributions have played a crucial role in enhancing our knowledge of PD and its associated disorders, including neuromuscular diseases and neurosarcoidosis (Reichmann et al. 1993a, 1995). Furthermore, his research delved into the treatment methods for gastrointestinal dysfunction in PD, offering valuable insights into the development of novel therapeutic strategies and future research directions (Klingelhoefer and Reichmann 2015; Reichmann 2021).
Beyond the traditional focus on motor impairments and dopamine replacement therapy, emerging research underscores the significance of cognitive and social functioning alterations in PD. These changes are believed to stem from disrupted activity within cortical and subcortical brain structures (Battaglia et al. 2023c, d, 2024d; Battaglia and Thayer 2022). Consequently, there is a growing imperative to develop holistic management strategies for PD that encompass not only motor symptoms but also address the cognitive and social challenges faced by individuals living with the disease (Candini et al. 2021; Di Gregorio et al. 2024; Tortora et al. 2023; Di Gregorio and Battaglia 2023). Additionally, rehabilitation programs, including speech therapy, occupational therapy, and physical therapy, are recommended as complementary treatments to help manage the functional limitations associated with the disease (Weiner and Singer 1989; Riklan and Cooper 1961; Hunt 1988). Continued efforts have been made to discover novel therapeutic approaches, with a growing interest in investigating the role of gastrointestinal dysfunction and autonomic disorders (Camilleri 1990; Goetz et al. 1986).
The function of energy metabolism
Energy metabolism, which involves the conversion of food and oxygen into energy and waste products within cells, is a fundamental process necessary for proper functioning of the brain and body (McKenna et al. 2012; Wagner et al. 2011; Laurindo et al. 2023a, 2024; Bosso et al. 2023). PD disrupts motor and coordination functions as well as other aspects, arising from the loss of dopamine-producing neurons in the substantia nigra, which is responsible for regulating motor control activity in other brain regions (Mazzoni et al. 2012; Ingvarsson et al. 1997; Zgaljardic et al. 2003; Castrioto et al. 2016). Prior to Reichmann’s research, we had knowledge of impaired energy metabolism in PD; however, the underlying mechanisms remain unclear (Cohen 1983; Heikkila et al. 1984).
Reichmann’s extensive research has primarily concentrated on three crucial aspects related to PD. Firstly, his investigations into energy metabolism have provided valuable insights into the underlying mechanisms of this neurodegenerative disorder (Reichmann and Janetzky 2000; Reichmann 2016, 2017; Klingelhoefer and Reichmann 2015). By studying the cellular processes involved in energy production and utilization within the brain, he has been able to identify key mitochondrial metabolic dysfunctions that contribute to the development and progression of PD. His findings have shed light on how alterations in energy metabolism impact neuronal function and survival, thus paving the way for potential therapeutic interventions targeting these pathways.
Previous hypotheses and findings
The following are some of the hypotheses and findings that had been proposed or uncovered prior to Reichmann’s research. Patients diagnosed with PD exhibit lower levels of glucose and oxygen consumption in the brain, particularly in the striatum, which is the primary target of dopamine neurons (Kuhl et al. 1984; Wolfson et al. 1985). This suggests that brain cells are less active and more efficient in their energy utilization. Additionally, individuals with PD have lower levels of the primary energy currency of the cell, adenosine triphosphate (ATP), and higher levels of anaerobic glycolysis byproduct lactate (Reichmann and Janetzky 2000; Gille et al. 2004; Emamzadeh and Surguchov 2018). These findings indicate that the cells are relying more on the less efficient anaerobic pathway to produce energy and that there exists an imbalance between energy supply and demand.
Meanwhile, patients with PD exhibit elevated levels of oxidative stress, which is the harm caused by reactive oxygen species (ROS) on cellular components, such as DNA, proteins, and lipids (Weng et al. 2018; Dorszewska et al. 2021; Chang and Chen 2020; Laurindo et al. 2023a; Nunes et al. 2023; Reichmann and Riederer 1989; Schapira et al. 1989; Mizuno et al. 1989). ROS are ordinarily generated during cellular respiration, but they can also be produced by environmental toxins, inflammation, or mitochondrial dysfunction (Franco et al. 2009; Chelombitko 2018; Cui et al. 2012; Laurindo et al. 2023b; Nishikito et al. 2023; Minniti et al. 2023; McGeer et al. 1988; Pan-Montojo et al. 2012). Oxidative stress can disrupt the function and structure of mitochondria, which are organelles responsible for producing the majority of the ATP in the cell (Cui et al. 2012; Federico et al. 2012; Guo et al. 2013). In PD patients, there is mitochondrial dysfunction, which involves the impairment of the mitochondrial respiratory chain, a series of enzymes and molecules that transfer electrons from glucose and oxygen to produce ATP and water (Bose and Beal 2016; Hu and Wang 2016; Malpartida et al. 2021; Tanaka et al. 2022b). This impairment can reduce the efficiency and capacity of energy production and increase the production of ROS and other toxic metabolites (Moradi Vastegani et al. 2023; Indo et al. 2007; Lee and Kim 2022; Laurindo et al. 2023a). The dysfunction of mitochondria can initiate cell death pathways, including apoptosis and necrosis (Lemasters et al. 1999; Bock and Tait 2020; Harrington et al. 2023). Individuals with PD have genetic mutations or polymorphisms that impact the enzymes or proteins involved in energy metabolism, such as complex I of the mitochondrial respiratory chain, pyruvate dehydrogenase, or uncoupling proteins (Tryphena et al. 2023; Buchanan and Taylor 2020; Kumar et al. 2022a). These genetic factors can alter the expression, activity, or regulation of these molecules, and disrupt the equilibrium and flow of energy metabolism.
Dr. Reichmann’s comprehensive research on energy metabolism in Parkinson’s disease
Reichmann’s research explored the thermodynamic, circadian, and molecular aspects of energy metabolism in PD (Mesika and Reichmann 2019; Hermann et al. 2020; Riederer et al. 2019). He conducted research on the impact of variables such as temperature, time of day, and genetic differences on the production and consumption of energy in brain cells. Additionally, he explored the relationship between energy metabolism in brain cells and inflammation, oxidative stress, and mitochondrial dysfunction, which are factors associated with PD (Bendig et al. 2024; Mesika and Reichmann 2019; Reichmann and Janetzky 2000; Laurindo et al. 2023a).
Reichmann and Riederer’s work in 1989 provided crucial biochemical analyses of respiratory chain enzymes in various brain regions of PD patients, highlighting deficiencies in the electron transport chain (Reichmann and Riederer 1989). Building on this foundation, Schapira et al. identified a marked reduction in the 30-, 25-, and 24-kDa subunits of mitochondrial complex I specifically in the substantia nigra of PD patients. This discovery linked mitochondrial dysfunction, particularly within complex I, to the pathogenesis of PD (Schapira et al. 1989). Furthermore, Mizuno et al. (1989) confirmed these findings, solidifying our understanding that impaired energy production within neurons due to complex I deficiencies is a critical factor in the development and progression of PD (Mizuno et al. 1989; Mizuno 1990). Through his investigation of these aspects of energy metabolism, he uncovered significant findings regarding the underlying causes and consequences of PD at cellular and molecular levels.
Furthermore, his work explored the potential benefits of various interventions aimed at safeguarding neurons from harm or enhancing their energy metabolism in PD. They investigated the impact of coenzyme Q10, a natural antioxidant and cofactor of the mitochondrial respiratory chain, which is involved in energy production (Gille et al. 2004; Beal et al. 1994). He also investigated the effects of creatine, a natural compound that can increase energy storage and availability in brain cells (Löhle and Reichmann 2010). Additionally, the effects of ketogenic diets have been explored, which are high-fat, low-carbohydrate diets that can induce the production of ketone bodies that are alternative energy sources for brain cells (Włodarek 2019; Phillips et al. 2018; Shaafi et al. 2016). His research has made a substantial contribution to our understanding of the etiology and pathophysiology of PD as well as the management of its symptoms and complications, providing new avenues for the development of effective therapies for PD by modulating the energy metabolism.
Premotor symptoms
Premotor symptoms are indicators that occur prior to the emergence of the primary motor symptoms of PD, such as tremors, muscle rigidity, and slowed movement (Chen et al. 2013; Rodríguez-Violante et al. 2017; Silva et al. 2023). These symptoms may also encompass non-motor-related manifestations, such as a decreased sense of smell, constipation, rapid eye movement (REM) sleep behavior disorder, depression, anxiety, exhaustion, and cognitive decline (Lee and Koh 2015; Kumaresan and Khan 2021; Radad et al. 2023; Tanaka and Chen 2023). Additionally, subtle motor changes, such as a reduction in arm swinging motion, micrographia, and facial masking, may also be present in the early stages of PD (Wu et al. 2015; Simonet et al. 2021; Lee 2023). Prior to Reichmann’s research, it was widely acknowledged that premotor symptoms were common in PD patients and frequently went unnoticed, with some cases displaying a lag of several years or even decades before the onset of motor symptoms.
Dr. Reichmann’s contributions to the understanding of premotor symptoms in Parkinson’s disease
Reichmann has made significant contributions to the understanding of premotor symptoms associated with PD (Reichmann 2010, 2017, 2021; Maass and Reichmann 2013; Buhmann et al. 2018; Storch et al. 2013). Through careful examination and analysis of prodromal stages, prior to the onset of motor symptoms, he has unveiled a range of non-motor manifestations that can serve as early indicators of the disease. Such symptoms include olfactory dysfunction, constipation, sleep disturbances, and cognitive impairments. By identifying these premotor signs, Reichmann’s work enhances the prospects of early detection and intervention, enabling early treatment and potentially delaying the onset of motor symptoms. His expertise in the premotor diagnosis of PD was evidenced by his comprehensive review of the current knowledge and challenges associated with this area of study. He specifically focused on the most common premotor symptoms, including hyposmia, constipation, REM sleep behavior disorder, and depression (Reichmann 2010, 2017; Ziemssen and Reichmann 2007; Reichmann et al. 2009). However, he emphasized the need for further validation and standardization of these methods. He was also involved in several international collaborations and projects on premotor PD, including the European Academy of Neurology (EAN) task force on the definition of premotor and prodromal PD and the International Parkinson and Movement Disorder Society (MDS) project on the development of clinical criteria for prodromal PD.
The etiopathogenesis and treatment of Parkinson’s disease
Prior to Reichmann’s research, the etiopathogenesis of PD was primarily understood through the recognition of motor symptoms such as tremors, lack of movement, and drooling, as documented in historical medical treatises dating back to ancient times. Early treatments for PD were based on empirical observations, with anticholinergic drugs introduced as far back as the 19th century (Case 1893; Rose and Brackenridge 1881; Barrett et al. 2021). The use of levodopa by Carlsson in 1958 revolutionized PD treatment; however, limited treatment options persist (Foley 2003). By the late 1980s, deep brain stimulation had emerged as a potential therapeutic approach (Siegfried and Rea 1988; Bronstein et al. 2011; Bucur and Papagno 2023; Benabid 2003).
A number of genetic risk factors have been discovered: Mutations in genes, including SNCA, PARK2, PINK1, PRKN, and LRRK2, have been linked to familial PD, and some of these genes also play a role in sporadic cases (Cherian and Divya 2020; Tan and Skipper 2007; Cherian et al. 2023; Lesage and Brice 2012). LRRK2 mutations are the most common genetic cause of both familial and sporadic PD (Martin et al. 2014; Kluss et al. 2019). LRRK2 is a protein that has multiple functions in the cell, such as regulating the activity and recycling of lysosomes, which are involved in breaking down and disposing of waste materials (Madureira et al. 2020; Roosen and Cookson 2016; Bonet-Ponce and Cookson 2022). LRRK2 mutations can affect the function of lysosomes and cause them to release toxic substances that damage neurons (Skibinski et al. 2014; Yakhine-Diop et al. 2014; Jeong and Lee 2020). LRRK2 mutations can also activate microglia, which are immune cells in the brain that normally clear away debris and pathogens (Schapansky et al. 2015; Moehle et al. 2012; Panagiotakopoulou et al. 2020). However, when microglia are overactivated, they can produce inflammatory molecules that harm neurons and contribute to neurodegeneration (Lull and Block 2010; Song and Colonna 2018; Xu et al. 2021). Therefore, LRRK2 mutations can play a role in the etiopathogenesis of PD by impairing lysosomal function and triggering neuroinflammation. Future disease-modifying therapies may be aided by the active research of Reichmann and colleagues concerning the genetic basis of PD, including the function of LRRK2 mutations (Biskup et al. 2008; Reichmann and Jost 2023b; Schapira et al. 2009).
Dr. Reichmann’s contributions to Parkinson’s disease treatment
Reichmann has significantly advanced the treatment of PD. His innovative research has focused on developing novel treatment strategies to enhance the management of PD symptoms. One of his primary research interests is the investigation of monoamine oxidase B (MAO-B) inhibitors, including selegiline and rasagiline (Antonini et al. 2018; Reichmann 2016; Gerlach et al. 2012). MAO-B inhibitors have been shown to be neuroprotective in cell culture and animal experiments, raising the prospect that they may also be neuroprotective in humans and potentially delay disease progression (Nagatsu and Nakashima 2020; Dezsi and Vecsei 2017; Szökő et al. 2018; Tábi et al. 2020). MAO-B inhibitors can provide more sustained and continuous stimulation to post-synaptic dopaminergic receptors by increasing dopamine’s half-life in the basal ganglia (Löhle and Reichmann 2011; Reichmann et al. 2005b; Ossig and Reichmann 2015b; Nagatsu and Sawada 2006). Therapeutic strategies, such as cell-based dopamine substitution methods, are currently being researched extensively (Barker 2019; Chen et al. 2018; Rodríguez-Pallares et al. 2023). These methods are intended to improve symptom management in PD patients. Other studies have also shed light on the role of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), in the development of PD, highlighting their potential as theraeutic targets (Evans and Barker 2008; Palasz et al. 2020; Khan et al. 2023).
Reichmann’s work has not only contributed to the optimization of treatment approaches for PD but has also offered hope for better symptom control and an improved quality of life for patients (Reichmann et al. 2005a, 2020; Antonini et al. 2023). His research has addressed the current limitations in the management of PD, where available treatments mainly focus on symptomatic relief and do not alter the course of the disease. His efforts have been instrumental in paving the way for potential disease-modifying treatments that could restore dopaminergic tone in a targeted, physiological manner, as well as identify drugs capable of preventing or slowing ongoing neurodegeneration (Battaglia et al. 2024b). His work has thus been pivotal in driving the development of new and promising treatment approaches that may lead to a transformative shift in the landscape of PD management in the coming years.
Furthermore, he emphasizes the importance of individualized treatment strategies for PD patients. Patients diagnosed with PD must be treated individually based on their predominant symptoms and clinical presentation (Dias et al. 2021; Lemke et al. 2005; Antonini et al. 2023). A broad understanding of medical treatment options, as well as invasive therapeutic approaches, is required to support patients and improve their quality of life. Thus, Reichmann’s work has made significant contributions to our understanding of PD etiology and treatment approaches.
Opening future research directions: Dr. Reichmann’s insights into tryptophan metabolism in Parkinson’s disease
The pathophysiology of PD has focused on the disruption of essential amino acids, including tyrosine and tryptophan (Trp) (Nagatsu et al. 2019, 2022; Nakashima et al. 2013). Trp, an essential amino acid, plays a pivotal role in various biological processes. It is a critical component of our diet and is integral to protein synthesis (Barik 2020; Kałużna-Czaplińska et al. 2019; Fiore and Murray 2021). Beyond its nutritional role, Trp is the precursor to several important molecules, including serotonin, a neurotransmitter that regulates mood, sleep, and other functions (Peters 1991; Galla et al. 2021). Abnormal Trp metabolism has been linked to a number of neuropsychiatric disorders, highlighting its importance in maintaining mental health (Davidson et al. 2022; Comai et al. 2020; Dell’Osso et al. 2016; Fiore and Murray 2021). PD is one of the disorders in which Trp plays an important role. More and more evidence suggests that changes in Trp metabolism may contribute to the disease’s pathogenesis, opening up new avenues for treatment neuropsychiatric disorders (Heilman et al. 2020; Huang et al. 2023; Li et al. 2022; Modoux et al. 2021).
Tyrosine hydroxylase (TH) plays a crucial role as the rate-limiting enzyme in the biosynthesis of dopamine. In 1988, Mogi et al. published a significant paper that described the decrease in both the amount and function of TH in the substantia nigra of patients with PD (Mogi et al. 1988; Tábi et al. 2020). The study highlighted the loss of dopaminergic neurons and the related processes of neurodegeneration. Remarkably, the level of TH activity per enzyme was discovered to be increased in the PD-affected brain, suggesting the potential presence of a compensatory mechanism (Mogi et al. 1988). This study emphasizes how the degeneration of TH-positive neurons directly impacts dopamine production, contributing to the motor symptoms characteristic of PD. Reichmann’s research provides novel insights into the neuroprotective and neuron-differentiating properties of 9-methyl-β-carboline (9-me-BC), a Trp-derived molecule (Fig. 2) (Polanski et al. 2010; Keller et al. 2020; Wernicke et al. 2010). His findings show that 9-me-BC has the potential to increase the differentiation of dopaminergic neurons (Polanski et al. 2011; Hamann et al. 2008). This study is critical for understanding the therapeutic options for PD because it shows not only the stimulatory effects of 9-me-BC on dopaminergic neurons, but also its protective and regenerative properties. Reichmann’s research suggests a promising future for treating neurodegenerative diseases by increasing the expression of TH and its transcription factors, with 9-me-BC leading the way as a potential anti-Parkinsonian agent.
The Trp metabolic pathways produce various metabolites that affect brain function and lead to in neurodegenerative disorders, including PD (Fig. 3) (Hestad et al. 2022; Heilman et al. 2020; Davidson et al. 2022; Tanaka et al. 2021a). PD patients exhibit altered levels of KYN metabolites in both the plasma and cerebrospinal fluid, and these changes are associated with symptom severity and nigral pathology (Heilman et al. 2020). Researchers have discovered a new mechanism by which mutations in the parkin gene, which cause familial forms of PD, disrupt the interactions between lysosomes and mitochondria, leading to impaired Trp metabolism and mitochondrial dysfunction (Peng et al. 2023; Mizuno et al. 2008; Chithra et al. 2023; Polyák et al. 2023). Scientists have identified the structures of chemicals that can inhibit tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase 1 (IDO1) which convert Trp into neurotoxic kynurenine (KYN) metabolites (Table 1) (Thackray et al. 2008; Tutakhail et al. 2020; Kozlova and Frédérick 2019). The majority of the compounds tested are for cancer treatment, but at least 12 antagonists targeting TDO and IDO1 have entered clinical trials (Sari et al. 2019; Peng et al. 2022). Some substances were shown to protect neurons from degeneration in a mouse model of PD (Perez-Pardo et al. 2021; Boros and Vécsei 2021; Ning et al. 2021). In addition to TDO and IDO1, kynurenine-3-monooxygenase has the potential to be another Trp-KYN pathway target for disease intervention. Furthermore, research has also uncovered new insights into the role of α-syn, a key pathological protein in PD, in regulating dopamine and serotonin metabolisms (Perez et al. 2002; Miquel-Rio et al. 2023). These findings suggest that targeting α-syn may modulate the production of neuroprotective or neurotoxic metabolites.
Tryptophan-kynurenine metabolism in Parkinson’s disease: emerging research and therapeutic opportunities
Meanwhile, emerging research has highlighted the dysregulation of the Trp–KYN metabolic system in the pathogenesis of PD (Lim et al. 2017; Venkatesan et al. 2020 Török et al. 2022). The metabolism of Trp along the KYN pathway plays a pivotal role in modulating neuroinflammation and oxidative stress levels within the central nervous system (Tutakhail et al. 2020; Mithaiwala et al. 2021; Mor et al. 2021; Tajti et al. 2023; Tanaka et al. 2024b). The clinical manifestations of disrupted KYN metabolism encompass a spectrum of cognitive impairments commonly observed in neurological and psychiatric disorders (Battaglia et al. 2023a, b, 2024c; Ippolito et al. 2022). These include deficiencies in memory consolidation and learning, compromised executive function leading to difficulties in planning and set-shifting, challenges in adapting behavior to environmental cues, as well as impaired working memory and emotional regulation (Battaglia et al. 2022a, b, c; Sellitto et al. 2022). Such cognitive deficits often manifest as a distinct pattern indicative of frontal lobe dysfunction (Battaglia 2022; Battaglia et al. 2022d), reflecting the intricate interplay between neurotransmitter dysregulation and neural circuitry alterations (Battaglia et al. 2022e, 2023e; Tanaka et al. 2023a; Balogh et al. 2021; Liloia et al. 2024).
Recent research has challenged the oversimplified classification of KYN metabolites as either neurotoxic or neuroprotective. Emerging evidence highlights their multifaceted roles (Leon-Letelier et al. 2023; Ramírez Ortega et al. 2021). These bioactive compounds have a wide range of properties, including the ability to modulate oxidative stress, reduce inflammation, and modulate immunity (Tan et al. 2022; Carreño et al. 2022). Their actions depend on concentration gradients and the cellular microenvironment (Valvo et al. 2022; Kaymak et al. 2021). Moreover, the metabolic system operates via complex feedback loops. Despite ongoing investigations, consensus regarding the precise functions of KYN metabolites remains elusive (Tanaka et al. 2021b). Understanding this complexity is crucial for developing targeted therapies in PD. Emerging research suggests that modulating this pathway could offer therapeutic benefits, potentially slowing disease progression and improving patient outcomes. Future studies are essential to further elucidate the mechanisms by which KYN metabolites influence neuronal survival and to develop targeted interventions. By advancing our knowledge in this area, we can pave the way for novel treatments that harness the Trp-KYN metabolism, offering hope to those affected by this debilitating condition.
Kynurenic acid and kynurenic acid analogs
Kynurenic acid (KYNA), a metabolite of the KYN pathway, has demonstrated neuroprotective effects in neurodegenerative diseases by regulating glutamatergic systems (Fig. 3) (Wang et al. 2015; Tanaka et al. 2020), and preventing dopaminergic cell death (Klein et al. 2013; Beggiato et al. 2013; Zaiter et al. 2021). Some of the potential benefits of KYNA analogs in the treatment of neuropsychiatric diseases are that they may improve the cognitive functions (Martos et al. 2022; Urbańska et al. 2021; Tanaka et al. 2022d). They may reduce oxidative stress and α-syn aggregation, which are major causes of neuronal damage and death in PD. They may modulate glutamate receptors and prevent excessive glutamate release and excitotoxicity, which can impair synaptic plasticity and learning in PD patients (Battaglia et al. 2024a). They may inhibit the formation of amyloid-beta fibrils, which are another type of toxic protein aggregates that impair neuronal function in PD. KYNA analogs are promising candidates for the development of novel drugs or supplements for PD as they may target multiple mechanisms of neurodegeneration and provide neuroprotection (Szabo et al. 2023; Majerova et al. 2022; Martos et al. 2024). However, further research is required to validate their safety and efficacy in patients with PD.
Researchers have been developing KYNA analogs to treat neurologic and psychiatric disorders (Tajti et al. 2015; Deora et al. 2017; Stone 2000; Kozak et al. 2014; Tanaka et al. 2022a). KYNA is a natural metabolite of Trp that has neuroprotective and anti-inflammatory effects, but it has low bioavailability and brain penetration (Bratek-Gerej et al. 2021; Lee et al. 2019; Ostapiuk and Urbanska 2022Török et al. 2020). KYNA analogues are specifically engineered to address these constraints and engage with KYNA receptors, including NMDA and GPR35 receptors, which play a crucial role in neuronal signaling and plasticity (Molnár et al. 2021). One of the KYNA analogs that has shown promising results is SZR-104, which can cross the blood-brain barrier and modulate the activity of KYNA receptors. SZR-104 is derived from KYNA and has similar neuroprotective and anti-inflammatory properties (Molnár et al. 2021; Szabo et al. 2023). In preclinical studies, SZR-104 improved energy homeostasis, and decreased neuroinflammation (Poles et al. 2021; Szabo et al. 2022). SZR-104 also affected the morphology and function of microglia, which are immune cells in the brain that can either protect or damage neurons (Szabo et al. 2022; Poles et al. 2021).
Another KYNA analog that has shown promising results is a series of multifunctional compounds that combine the structural features of KYNA and tacrine, a drug that inhibits cholinesterase, an enzyme that breaks down acetylcholine, a neurotransmitter that is important for memory and cognition (Gorecki et al. 2021; Lustikaiswi et al. 2021; Decker and Duncan 2020). These compounds have high brain permeability and antioxidant activity, and they can inhibit both cholinesterase and amyloid beta peptide, which are associated with AD. These compounds also have high affinity and selectivity for the alpha-7 nicotinic receptor, which is a potential target for cognitive enhancement (Cieslikiewicz-Bouet et al. 2020; Singh et al. 2023). These KYNA analogs and KYNA combinations could be potential candidates for the treatment of neurodegenerative disorders, as they have multiple beneficial effects on the brain. However, further studies are needed to confirm their safety and efficacy in humans.
Investigation into the KYN metabolism has recently emerged as a promising approach for comprehending and potentially tackling crucial aspects of PD that have been at the forefront of Reichmann’s research. The KYN metabolism, involved in the degradation of Trp and the synthesis of various metabolites, has been increasingly linked to the onset of PD, regulation of energy homeostasis, and the emergence of early symptoms. Research has emphasized the connection between KYN metabolites, the process of aging, and the onset of PD, providing insight into its possible involvement in the progression of the disease. Furthermore, the metabolic pathway’s crucial role in producing compounds that regulate energy balance has been recognized, emphasizing its broader impact on physiological functions. The study of KYNA analogs, which are artificially created molecules intended for their positive impacts, has shown promise in advancing the development of drugs for potential treatment of neuropsychiatric disorders. This line of research may reveal new targets for treating PD by exploring the complex links between the KYN pathway, energy balance, and the early stages of PD. The findings could lead to more efficient and focused interventions for PD.
Discussion
The research conducted by Reichmann has greatly enhanced our comprehension and therapeutic approaches towards PD. The researcher’s findings have provided insight into the disturbance of energy metabolism in PD, a crucial process for the optimal operation of the brain and body. This disruption is caused by the degeneration of dopamine-producing neurons in the substantia nigra, a region responsible for regulating motor control in the brain. Before his research, it was understood that there was impaired energy metabolism in PD, but the specific mechanisms causing this impairment were not yet clear. Reichmann’s research has also emphasized the frequency of premotor symptoms in PD, which manifest before the appearance of main motor symptoms. This offers valuable knowledge about the initial phases of the illness. In addition, his research has enhanced our comprehension of the function of neurotrophic factors, such as BDNF, in the development of PD and their potential as a target for therapy. His work has not only provided optimism for enhanced management of symptoms and a higher standard of living for patients with PD, but also established the foundation for the creation of novel treatment approaches and potential therapies that can modify the progression of the disease.
Reichmann, a member of the editorial board of the Journal of Neural Transmission, collaborated with other experts to advance the understanding of PD etiology and expand its treatment options (Riederer et al. 2019; Sontag et al. 1995). For instance, He collaborated extensively with Dr. Peter Riederer to investigate several topics, including the etiology and treatment of PD, the function of iron in neurodegeneration, and the use of biomarkers for early detection of PD (Riederer et al. 2006; Reichmann et al. 2012a; Gerlach et al. 2012). Reichmann has co-authored papers with Dr. Kurt A. Jellinger on a variety of topics, including mitochondrial dysfunction, particularly in the electron transport chain and mitochondrial DNA, and its potential role in the pathogenesis of PD, as investigated using postmortem brain analysis of PD patients (Janetzky et al. 1994; Lestienne et al. 1990, 1991; Reichmann et al. 1993b).
Other co-authors include Ilona Csoti on the intersection of internal medicine and neurology and lifestyle and environmental factors in PD (Csoti et al. 2016; Reichmann et al. 2022); Wolfgang H. Jost on the latest developments and controversies in PD research (Reichmann and Jost 2023b); Christiana Ossig on neuropsychiatric symptoms in movement disorders and treatment strategies for advanced PD (Ossig et al. 2015; Ossig and Reichmann 2013); Jiri Koschel on lifestyle factors related to PD (Reichmann et al. 2022); Stefan Lorenzl on the high correlation between motor functions and quality of life (Krismer et al. 2022); Moussa BH Youdim on a comprehensive overview of current clinical and basic research on PD and related disorders (Riederer et al. 2006); Sofia B Dias and José A Diniz on potential for unobtrusive remote screening and detection of early PD signs (Iakovakis et al. 2018); Björn H. Falkenburger on translational research in PD (Dinter et al. 2020): Theodoros Kalliakoudas on homeostatic plasticity in the basal ganglia, which may explain non-classical PD (Falkenburger et al. 2022); Alexander Storch on sleep disorders in PD (Schrempf et al. 2014); Peter Vieregge on executive function differences in PD (Lange et al. 2003); and Christoph Schrader on the evidence-based guidelines for laboratory testing to diagnose, monitor, and manage PD (Müller et al. 2016), among others. Additionally, he has participated in a symposium focused on this topic, showcasing his commitment to advancing knowledge and improving treatment options for PD. These collaborations serve as testament to Reichmann’s dedication and expertise in this area.
A review of Reichman’s contributions to PD research could be a valuable and timely extension of previous work, providing a comprehensive overview of his pioneering studies on the role of α-syn in the pathogenesis of this neurodegenerative disorder. He has made substantial progress in understanding the mechanisms by which α-syn interacts with mitochondrial membranes, initiates protein synthesis, and leads to the death of dopaminergic neurons. In addition, his research has discovered new therapeutic targets and approaches, such as rapamycin and gene therapy, to control the levels of α-syn and hinder its aggregation. A review article of this nature would not only provide a comprehensive overview of the existing knowledge, but also emphasize the persisting obstacles and prospective avenues for further research on PD.
Generally, PD research has faced several challenges. The use of cellular models in preclinical research relies on specific culture conditions that may not accurately mimic the natural environment. These models often lack the ability to develop neuronal networks, resulting in the absence of essential connections. In clinical studies, the variability in diagnostic criteria for PD can impact the consistency of diagnoses across studies, affecting the reproducibility of research findings. PD’s diverse range of motor and non-motor symptoms complicates the development of comprehensive treatment approaches. Long-term studies, crucial for understanding PD progression, are difficult to maintain due to patient dropout and the need for extended funding and resources. Assessing the quality of life for PD patients remains challenging due to its subjective nature and the multifaceted impact of the disease on patients and caregivers. Additionally, while exploring the gut-brain axis in PD pathogenesis holds promise, the precise mechanisms linking gut dysfunction to PD development remain unclear.
This review has the potential to yield multiple advantages for both the scientific community and patients. At first, it presents a brief summary of Reichmann’s groundbreaking research on the importance of genetics in PD, with a specific emphasis on the mutations in the LRRK2 gene that are associated with both familial and sporadic forms of the condition. Furthermore, it has the potential to emphasize the deficiencies in knowledge and the obstacles that still exist in comprehending the molecular mechanisms and clinical significance of gene-environment interaction. In addition, it can suggest possible pathways and therapeutic strategies to manipulate the activity of gene and environmental interactions, thereby impeding or decelerating the onset and progression of PD. The primary objective of this research endeavor is to discover a remedy for PD, a profoundly debilitating neurodegenerative ailment that impacts a vast number of individuals globally. However, to accomplish this goal, it is essential to develop a thorough plan that combines genetic, biochemical, cellular, animal, and human studies with advanced techniques such as gene editing, stem cells, and biomarkers. The field of study is undergoing rapid development and holds significant promise for enhancing the identification, prediction, and management of PD. An article of this nature could offer a valuable synopsis and direction for researchers and clinicians with an interest in this subject matter.
Some possible limitations are that this review article may not cover all the aspects of PD research, including other environmental factors, biomarkers, or other genetic causes. It may also not reflect the latest findings or controversies in the field, as research is constantly evolving. Some possible benefits are that this review article could provide a comprehensive and authoritative overview of Reichman’s work on PD. It could also highlight the novel therapeutic targets and strategies that Reichman has identified. Some potential translation into clinical practice is that the review article could inform and guide clinicians and researchers who are interested in this topic and inspire new collaborations and innovations (Tanaka et al. 2022c, 2023a, c, d, 2024a; Tanaka and Vécsei 2024). It could also raise awareness and interest among patients and the public and thus encourage participation in clinical trials and studies. The review article could ultimately contribute to the development of more effective and personalized treatments for PD, a devastating neurodegenerative disorder that affects millions of people worldwide.
Conclusion
Reichmann’s pioneering research in PD has significantly advanced our understanding of this complex neurodegenerative disorder. His research into energy metabolism, premotor symptoms, and the multifactorial nature of PD has yielded valuable insights that have the potential to transform the landscape of PD management. His research into the underlying mechanisms of PD paved the way for the development of novel therapeutic approaches and personalized treatment strategies. His research not only sheds light on the pathophysiology of PD, but it also provides hope for better diagnostics, symptom control, and, ultimately, an improved quality of life in patients. Future-oriented, his work emphasizes the importance of multifaceted treatment approaches that consider not only motor symptoms but also cognitive and social dysfunction that people with PD face. His findings can be expanded upon in future PD research to enhance our comprehension of the condition and create more potent therapies. By continuing to investigate new therapeutic targets and approaches, we can work toward a future in which personalized and targeted interventions open up new avenues for research on Trp metabolism and related analogs, promising better outcomes for people with PD.
Abbreviations
- α-syn:
-
Alpha-synuclein
- ATP:
-
Adenosine triphosphate
- BDNF:
-
Brain-derived neurotrophic factor
- DDI:
-
Dopa decarboxylase inhibitor
- IDO1:
-
Indoleamine 2,3-dioxygenase 1
- KYN:
-
Kynurenine
- KYNA:
-
Kynurenic acid
- MAO-B:
-
Monoamine oxidase B
- 9-me-BC:
-
9-methyl-β-carboline
- PD:
-
Parkinson’s disease
- REM:
-
Rapid eye movement
- ROS:
-
Reactive oxygen species
- TDO:
-
Tryptophan 2,3-dioxygenase
- TH:
-
Tyrosine hydroxylase
- Trp:
-
Tryptophan
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This work was supported by the National Research, Development, and Innovation Office—NKFIH K138125, SZTE SZAOK-KKA No: 2022/5S729, and the HUN-REN Hungarian Research Network.
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Tanaka, M., Vécsei, L. Revolutionizing our understanding of Parkinson’s disease: Dr. Heinz Reichmann’s pioneering research and future research direction. J Neural Transm (2024). https://doi.org/10.1007/s00702-024-02812-z
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DOI: https://doi.org/10.1007/s00702-024-02812-z