Frontiers in Clinical Drug Research - CNS and Neurological Disorders: Volume 10

Atta-ur-Rahman, Zareen Amtul

• Editore: Bentham Science Publishers
• Anno: 2001
• ISBN:
  9789815040678
• Argomento: Sciences physiques
• Categoria: Chimie clinique

Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a book series that brings updated reviews to readers interested in advances in the development of pharmaceutical agents for the treatment of central nervous system (CNS) and other nerve disorders. The scope of the book series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of contemporary molecular targets involved in neurological and CNS disorders. Reviews presented in the series are mainly focused on clinical and therapeutic aspects of novel drugs intended for these targets. Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critical information for developing clinical trials and devising research plans in the field of neurology. Volume 10 of the series continues to present novel information about new and interesting approaches to treat common neurological disorders, with a focus on neurodegeneration and pain medicine. The volume presents 7 detailed reviews in total. - Neurodegenerative disease: prevention and treatment through plant extracts therapy
- Emerging novel approaches and recent advances in Parkinson's disease treatment and diagnosis
- Neurotrophic factors to combat neurodegeneration
- Neural bases of executive function in ADHD children as assessed using FNIRS
- Modulation of mesenchymal stem cells, glial cells and the immune system by oligodeoxynucleotides as a novel multi-target therapeutic approach against chronic pain
- Chronic pain: focus on anticonvulsants
- A review of the impact of testosterone on brain and aging-related decline in brain behavioural function

Emerging Novel Approaches and Recent Advances in Parkinson’s Disease Treatment and Diagnosis

Virendra Tiwari^{1, 2, *}, Akanksha Mishra^{1, 4, *}, Sonu Singh^{1, 3}, Parul ¹, Pratibha Tripathi¹, Shubha Shukla^{1, 2, #}

¹ Neuroscience and Ageing Biology Division, CSIR- Central Drug Research Institute, Lucknow 226031, U.P., India

² Academy of Scientific and Innovative Research (AcSIR),Ghaziabad 201002, India

³ Department of Neuroscience, School of Medicine, University of Connecticut (Uconn) Health Center 263 Farmington Avenue L-4078 Farmington CT 06030, USA

⁴ Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease (AD). Recent data suggest that more than 6 million people worldwide have PD. The death of midbrain dopaminergic (DAergic) neurons in substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA), and loss of their terminal in the striatum region lead to motor and non-motor impairments in PD. Currently, several pharmacological drugs acting as dopamine agonists, dopamine reuptake inhibitors, and dopamine breakdown inhibitors are available for the treatment of PD patients. However, all these treatments only provide symptomatic relief without halting the process of neurodegeneration. They are widely associated with unwanted side effects such as orthostatic hypotension, hallucinations, somnolence, levodopa (L-DOPA)-induced dyskinesia, and impulse control disorder. This article discusses the biochemical and physiological mechanism(s) of PD pathogenesis and how the emergence of the new target and drug identification are advancing our knowledge for the development of novel PD therapies. The current data obtained from animal models and clinical research suggest that early treatment may be one of the effective strategies in PD management. Recent stem cell progenitor cell transplantation studies have added an extra layer in future treatment approaches by showing very promising results and outcomes in PD patients. Apart from classical dopamine receptor modulators as drug treatments, recent data suggest that PD pathogenesis can also be managed by targeting neurogenesis, apoptotic pathway, neuroinflammation, mitochondrial biology, and oxidative damage. Therefore, identification of reliable disease markers and putative drug targets to halt the process of neurodegeneration and genetic profiling of individuals will help in finding new avenues in PD treatment.

Keywords: Dopamine, Dopamine Agonists, Neurodegeneration, Parkinson’s Disease, Pharmacological Treatment.

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^# Corresponding Author Dr. Shubha Shukla: Principal Scientist, Neuroscience and Ageing Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow-226031, Uttar Pradesh, India; Tel: [phone]; Fax: [phone]; E-mail: [email protected]^* These authors have equal contribution.

INTRODUCTION

Parkinson^’s disease (PD) is an age-related CNS disorder characterized by depletion of dopaminergic neurons in the substantia nigra (SN) region of the brain, which leads to a marked decline of dopamine (DA) neurotransmitters in the striatum. Due to deficiency of DA supply to the striatum, an imbalance occurs between neurotransmitters acetylcholine (ACh) and dopamine (DA), subsequently resulting in classical PD symptoms manifested as tremor, akinesia, postural hypotension [1^-3]. The principal approaches applied in the management of PD symptoms by drugs that either prompt the release of dopamine or increase dopamine concentrations at receptors [4, 5]. Widespread downregulation of dopaminergic neurons increases with precarious onset in middle age to late adulthood. The mechanisms involved in the downregulation of dopaminergic neurons in PD patients are oxidative stress, mitochondrial dysfunction, neuroinflammation, excitotoxicity, imbalance of intracellular calcium, and iron homeostasis [6, 7]. Neurotoxin-based animal models have demonstrated themselves to be a reliable tool for investing in novel therapies and increasing the effectiveness of symptomatic treatment of PD [8]. The present therapeutic strategy against PD is mainly to restore the optimal dopamine(DA) level and its correlated signaling pathways in which levodopa, a precursor of dopamine(DA) is given to the PD patients [9]. Levodopa is given with carbidopa, a peripheral decarboxylase inhibitor that decreases the peripheral breakdown of L-Dopa and reduces the side effects of L-Dopa, mainly cardiovascular and gastrointestinal problems [10]. Another drug therapy for PD is monoamine oxidase B inhibitors(MAO-B), which inhibit DA metabolism which reinforces mitochondrial dysfunction and oxidative stress [11]. Further, a novel therapeutic option for PD is catechol-o-methyltransferase (COMT) inhibitors, which are administered with L-Dopa. COMT inhibitors prolong the action of L-Dopa, thus enhancing the duration of time a patient could take to benefit from L-Dopa [12, 13]. Another therapeutic approach for PD is dopamine receptor agonists, which directly stimulate the postsynaptic receptors in the striatum. They decrease the metabolism of dopamine and reduce free radical formation in the striatum [14]. Glutamate receptor antagonist is also given in PD, like amantadine, an antiviral drug that decreases motor and non-motor symptoms in PD patients, and akinesia is specifically treated by amantadine [15, 16].

Nowadays phytochemically active plant extracts and their secondary metabolites are being extensively used in PD therapy as these have substantial neuroprotective potential in PD [17]. Some important medicinal plants used in, which help in the mitigation of disease progression, are Ginkgo biloba, Bacopa monnieri, Curcuma longa, Camellia sinensis, green tea catechins, etc [9, 18^-21]. A study has shown that Mucuna pruriens contains Levodopa, which provides a long-term improvement in PD, with decreased risk of bradykinesia in the 6-OHDA lesioned model of PD [22], and has higher efficacy than levodopa [23].

Currently, the scientific community is focused on stem cell therapy for the treatment of PD. Stem cell transplantation is an easily accessible target for in vitro as well as in vivo systems. Neural stem cells have the innate ability to proliferate, migrate and differentiate into multiple cell lineages such as astrocytes, oligodendrocytes, and neuronal cells. A recent stu...