JOURNAL OF DRUG DELIVERY RESEARCH

eISSN 2319-1074

REVIEW ARTICLE

RECENT ADVANCEMENTS IN PARKINSON'S MANAGEMENT

Manoj Kumar Katual*1, S.L.Harikumar2

1-Rayat Bahra Institute of Pharmacy, Hoshiarpur, Punjab, India-146001.

2-University School of Pharmaceutical Sciences, Rayat-Bahra University, Mohali, Punjab.

Corresponding author: Manoj Kumar Katual

Publication history: Received on 18.3.2017 , Published online on 24.4.2017

ABSTRACT

Parkinsons disease is the major threat to the population more than 40 years of age. Parkinsons disease is occurring
due to dopamine deficiency, which is caused by the degeneration of nigrostriatal dopaminergic neurons. This causes
the major clinical motor symptoms of Parkinsons disease. Though the treatment methods are available, the
treatment of predominantly non-motor feature are remain a challenge which is caused by the degeneration of non-
dopaminergic neurons. The review focused on the challenges and important therapeutic advancements of the
disease. This article opens the view on different approaches for dopaminergic, non-dopaminergic drugs for
Parkinsons disease and use of novel drug delivery systems such as nanoparticle drug delivery. The motor
complications arise from the existing therapy can be controlled by various therapeutic approaches and drug delivery
systems. The non motor symptoms of the diseases (Commonly known as Frozen Addict) were poorly recognized
and inadequately treated. However, attention is now being focused on the non-motor symptoms, which may be the
ray of hope in the treatment of disease in new dimensions. This is the area which arose less concentrated in the
previous decades the need for newer and effective agents in the treatment. Still the extensive research has to be
focused further. The non pharmacological treatments also may explore in the near future like PD vaccine, Cell
transplantation, Gene therapy and surgical methods. The drug delivery system such as TDDS & Nanoparticles drug
delivery systems also contribute more for the novel approaches to eradicate the killer disease in coming decades.
Keywords: Neuro-behavioural disorders, Nigrostriatal dopaminergic neurons, Neuro-degenerative disorders,
Neurotoxins, SLN, Dyskinesia.

INTRODUCTION
In the world currently many people are affected by neurological disorders such as Alzheimer,
Parkinson's Disease, Cerebral ischemia and Brain Tumours. The treatment of these diseases is
found to be challenging since decades. The main challenge is how to penetrate the BBB (Blood
Brain Barrier) for drug delivery [1]. The recent advancements in understanding of these diseases
increase the interest in discovering newer molecules in this category which is evident by rapid
growth in the pharmaceutical of CNS related candidates. Though many drug candidates are
available it is still challenging to cross the blood brain barrier for drug delivery [2]. Various
strategies including invasive and non-invasive have been tried to overcome the biggest problem
that is a Blood Brain Barrier. Some of the feasible methods which are available includes
alternating lipophilicity, molecular weight, charge of active pharmaceutical ingredients. Invasive
methods include direct injection, osmotic opening, structural modification and chemical drug
delivery methods have tried. This article tries to enlighten various methods excepted for drug
delivery to the CNS [3].

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CNS barriers
The two main interfaces of brain, which protects neurons from the substances present in the
blood including drugs. it also helped in maintaining water homeostasis and proper milieu. These
are important for neuronal functions. Those are described as a Blood CSF interface and Blood
Brain Barrier.
Blood Brain Barrier
The BBB stand a major challenge for drug delivery to brain so that the treatment of
neurodegenerative disorders remains unsolved. the structure of the brain is very specific due to
tight junction or zonula occludens mainly composed of interconnected endothelial cells which
controls the passage of molecules. For more than 20years various efforts have performed to cross
the barrier. The current challenge is to deliver the drug molecule through BBB in a safe and
effective manner [1,4].
Brain Cerebrospinal Fluid
The Blood cerebrospinal fluid (approx. 140ml) acts as a supplement provider for brain and spinal
cord. The entire volume is produced and excreted to blood every 4-5 hours for a day. The
biological properties of CSF associated with initiation of brain neurogenesis. CSF is secreted by
the choroid plexus epithelium which is responsible for neuroendocrine signaling and
neuroimmune response [5,6].
The Primary Role of the BBB
BBB completely restricts the free movement of hydrophilic compounds it may be paracellular or
may be transcellular. BBB is responsible for the transport of essential nutrients and discharge of
metabolites [7]. Lipophilic molecules and gases (Carbon dioxide, Oxygen) communicated
through passive diffusion while glucose and amino acids require specific transport [8].
Drug Delivery to Brain
Multiple mechanisms have been approached for the drug targeting to the brain, but a great care
must be considered regarding the efficacy, biorecognization, toxicity and KDME of API.
Active targeting: In this method surface modification technique is employed to transport drug
with carrier to a specific site. It is of 3 types:
a) First order targeting
b) Second order targeting
c) Third order targeting
First order targeting is restricted towards availability of the system to a targeted organ or tissue.
In second order targeting differentiate specific delivery to cell vicinity. Third order targeting
includes intracellular localisation to gene or nucleus [5,11]. Further Active targeting
differentiated into following:
Ligand mediated targeting: A biologically active molecular ligand (e.g. Anti-body, Polypeptide)
helps the drug carrier system to reach their target [9,12].
Physical targeting: The environment changes (e.g. Light, Temperature, pH, Ionic strength,
Electric Field) employed to the establishment of drug carrier to pre-identified area.
Dual targeting: The synergistic effect takes the lead where the carrier having its own activity
increases the therapeutic efficacy of the drug [10,12].
Double targeting: An ideal combination of temporal and spatial methods to target a carrier
system which control the rate of drug delivery as well as specificity.
Passive targeting: The capability of Reticulo Endothelial System (RES) to engulf micro
particles make them an ideal substitute for hepatic targeting.

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Invasive targeting: By avoiding the passive uptake of colloids through RES, the normal
functioning is suppressed with the help of pseudo colloidal carrier [11,12].
Parkinson's Disease
Parkinson's Disease is a common neurodegenerative disorder in age group of 60-70 years. As per
statistics 1 in 500 in the US affected by PD, more prone to male than female (1.8 times). The
prevalence will increase in the coming future as per WHO estimated 10 million people
worldwide affected by PD which is not an uncommon disease [13].
The major factor for PD initiation is loss of dopaminergic neurons in the substantia nigra, located
in the basal ganglia, lower part of the human brain. Clinically evident Parkinson's are due to loss
of approx. 82% dopaminergic neuron. Initially developed by trauma in body part with stiffness
or slow movement ( dyskinesia at a later stage). The depletion of dopamine in the straitum is the
major cause of PD, additionally the presence of Lewy bodies in other cells. There is no current
treatment available for the prevention of PD progression [14,15].
Symptoms: The major symptoms are classified into motor and non-motor types.
Motor symptoms.
Bradykinesia : The slowness in the movement or limited range of movement caused by
bradykinesia can affect Parkinson's progress.
Rigidity: It causes stiffness and inflexibility of body parts which is uncomfortable and painful
(called as Frozen addict).
Tremor: Involuntary shaking, trembling of the muscles of hand and foot. It occurs in resting state
of the person.
Postural instability: At late stage of PD , the complaint of dizziness is common that is incapable
of maintaining an upright posture. This is also called retropulsion.
Non-motor symptoms.
The non-motor features apart from movement disorders, have a major impact on the quality of
life. Early recognition and treatment is useful to overcome this problem [16,17].
Causes
The exact causes of Parkinson's is still a mystery, but the multiple contribution of various factor
leads to PD development, which may be genetic or environmental or both.
Genetic: Eleven genes have been traced by genetic linkage and six genes identified as a probable
causative agent for the commencement of PD, i.e. -synuclein (SNCA), ubiquitin C-terminal
hydrolase like 1 (UCH-L1), Parkin (PRKN), LRRK 2, PINK 1 and DJ-1 genes. Among 6 genes
LRRK 2 gene (PARK8) is the most common cause for PD having the frequency approx. 7%. The
initiation of PD is associated with the degeneration of Dopaminergic neurons of substantia nigra.
With the continuous downfall the severity is directly proportional to dopamine deficiency and
may be corrected by immediate replacement with L-dopa. Studies reveal that a gene encoding -
synuclein (a lipid binding protein) identified as the basis for inheritance of PD. It is a major
component of Lewy bodies. Families with genomic triplication of -synuclein gene are more
susceptible. The study reveals the direct relationship between Parkin gene and PD. The
difference between Parkin linked PD and -synuclein linked PD is the absence of Lewy body. A
third gene responsible for PD deubiquitination enzyme UCH-L1 a mutant protein [13,18,19].
Environmental factors: The toxic chemicals like MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine) is a causative agent for initiation and development of PD. The exposure to
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) which is a neurotoxin capable of inducing
Parkinsonian in humans. This factor has been confirmed by various epidemiology studies which
reveals that the rural residence, well-water drinking and exposure to herbicides and pesticides

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play role in development of PD. The possible etiology of PD was traced to the compound MPTP
that is a contaminant to heroin substitute. It causes irreversible destruction of dopaminergic
neurons. MPTP converts to a toxic metabolite MPP+ by the enzyme monoamine oxidase (MAO).
MPP+ selectively acts on dopaminergic neurons and inhibits mitochondrial oxidation reactions.
Other herbicides such as rotenone also has proved to be a causative agent for PD [19,20].
Diagnosis
Unfortunately, there is no standard diagnostic testing for PD. The diagnosis of Parkinsons is
first made by an internist or family physician. Many people seek an additional opinion from
a neurologist with experience and specific training in the assessment and treatment of
Parkinsons disease referred to as a movement disorder specialist. To diagnose Parkinsons, the
physician takes a careful neurological history and performs an examination. Diagnosis of
Parkinsonian syndrome includes: Movement disorders, Muscular rigidity, Postural instability,
and Tremor [21,22].

RECENT DEVELOPMENTS IN PARKINSONIAN MANAGEMENT.

Currently, two new therapies found for the patients suffering from chronic progressive
neurological disease, i.e. PD, they are vaccines and monoclonal antibodies (MAb). A parenteral
MAb leads to a direct treatment, whereas the vaccines strengthen the immune system.
Collectively, they are called as immunotherapy for PD. The first MAb i.e. PRX002 for PD is
under trial. The recent research has reviled the connection between the intestinal microbiota
(microbes) with CNS, feasible causative agent for PD pathology [23,24].
Dopamine agonist monitoring strategy: The Dopamine agonist drugs strongly associated with
impulse control disorder. as per the FD report 2.7 million serious cases were reported between
2003 to 2012. These were due to dopamine receptor agonist and dopamine receptor drugs. So
strict monitoring is required before prescribing the above drugs [25,26].
Treatments available
Modern advancement for the treatment of PD includes neurological treatment (neurografting)
specific rehabilitation, specialist nursing, tributaries towards Parkinson's patient. The major
drawback for the treatment of PD based upon systemic uptake of API and redistribution across
the BBB and into CNS. A multidisciplinary approach has to be considered for multifactoral
syndromes of Parkinson's.
The major ambition of Parkinsonism therapy is to increase the dopamine level, stimulating the
arena of dopamine in the CNS, block the effects of Acetylcholine or other enzymes which reduce
the effectiveness [13,14].
Alternative therapies can be considered for direct intervention with CNS. These include
neurosurgical approaches which bypass the BBB. It requires implantations of IPG (implantable
pulse generator similar to a pacemaker producing electrical signals to brain for the stoppage of
dyskinesia) [17,18,21,22].
Advanced invasive techniques for Parkinsonism
Recently, some physical based techniques approached for mechanical breaching of BBB.
Intra-cerebro-ventricular (ICV) infusion
Convection-enhanced delivery (CED)
Microchip system or Implants
Disruption of BBB
All the above methods have employed for direct delivery of therapeutics in the CNS.
ICV infusion

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The therapeutics concentrate at a very low percentage of 1-2% in CSF in Brain. By general
circulation the therapeutics can distribute itself to BBB arena, so it can be predicted a slow i.v.
infusion can help to transport the drug to cross the BBB. But the pharmacological effect will be
synergies in combination with target receptor, meanwhile the conditions must be maintained and
the target receptor must deliver the therapeutic in close vicinity [27].
CED
Convection-enhanced delivery is an innovative idea of bypassing BBB by direct infusion into the
CNS. CED can be implemented by the help of a micro catherater insertion into brain parenchyma
for 2 hours for continuous infusion. With a limitation for right identification of location in brain
[28,29].
Implants
The successful implantations of intra-cerebral neurotrophins device can be helpful for the local
release in the brain. Biodegradable polymeric implant can be helpful in this approach. The
limiting capacity of this technique is related with implantation distance from desire [30,31]
Drugs available for the treatment of Parkinson's Disease.
a) Carbidopa / Levodopa Therapy (Carbidopa, Levodopa)
b) Dopamine agonists (Apomorphine hydrochloride, Bromocriptine, Ropinirole, Rotigotine)
c) Anti-cholinergics (Benzotropine mesylate)
d) MAO-B inhibitors (Selegiline)
e) COMT inhibitors (Entacapone, Tolcapone)
Disruption of BBB (BBBD)
BBBD has reported the most effective way for direct delivery of therapeutics inside the brain,
but it is not free from undesirable effects. The disruption of the BBB has an advantage to open
the tight junction between endothelial cells and brain capillary [32]. Various approaches for
BBBD are osmotic disruption, ultra sound disruption, application of bradykinenin. All the above
approaches leads to patient non-compliance, high cost of therapy, hospitalization requirement
and chances of permanent damage of neurons [33].
Non-invasive approaches and other routes for CNS drug delivery
Prodrug approach
Prodrug based CNS targeting has improved its characteristics, after undergoing the chemical
conversion. The metabolites produced acts as main active pharmacological agent. This prodrug
approach is a good idea to alternate or improve physicochemical properties. The Mechanism of
action of prodrug relies on closure and longer contact with the receptor. Example, the
accessibility of morphine through CNS only can be affected after acetylation of both hydroxyl
group i.e. prodrug of morphine. Still prodrug having some limitation that is alternation of
original tissue and of efficacy and toxicity of the parent drug. Sometimes it may cause increased
tissue burden [34,35].
Redox chemical delivery
It is a novelistic approach of targeting to a specific target organ by chemical reaction and enzyme
activation. The lies of bond lead to release of the API, it contains two moieties, one targeted
moiety responsible for site specificity where as the other is modifiable, serve as a protector
[36,37].
Pulmonary/Nasal delivery
This technique involves the delivery of drug through the respiratory tract so that it can reach to
the deepest layer, but having a constant of particular size and density. The drug particles must
have a nano scale range and a density of less than 0.4g/cm3. The choice of the drug of nasal route

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are phospholipids, amino acids or their combinations. The required dose is 33% of an oral dose
[38,39].

Receptor mediated delivery

This strategy is based upon the bonding between non-transferable protein/peptide to a
transferable protein/peptide with the help of transcytosis where a receptor or vector takes a lead
role to cross the BBB. A vector may be a modified protein or receptor specific monoclonal anti-
bodies. The above technique is based on chimeric peptide technology. Another approach is the
attachment of the drug with transporting an vector by an amide linkage so that the cleavability
will minimise [40].
Other approaches for drug delivery to Brain
Multiple attempts have tried with carrier mediated drug delivery to the CNS, they are briefly
discussed to know their agility in drug delivery to desired areas.
Liposomes
Liposomes are lipid bilayer vesicles first designed by Bangham. These are the vascular structure
consisting of an aqueous core covered with a hydrophobic lipid bilayer. The lipid employed are
phospholipids so that compatibility with biological components and minimising adverse effects.
Liposomes act as an ideal carrier for drugs, biotechnologicals, anti-cancer molecule as well as
micromolecules. The anti-cancer chemotherapy through liposomes reduce systemic toxicity. The
advantages with liposome is to incorporate both hydrophobic and hydrophilic molecules through
a single delivery having multiple options in size from 15nm to several mm. The wide range in
size and unique characteristics (both hydrophobicity and hydrophilicity) makes it more utilisable.
As per the recent study a nanosize liposomes (called nanoliposomes) show a selective tumor
localisation [41,42].
Nanoconjugates
As the name suggests nanoconjugates consists of covalently attached three functional domains,
i.e. targeting group, a linker and a drug. It gives tissue specificity and maximum efficacy. The
major concept behind is nanoconjugates is multitargeting [43,44].
Nanoparticles
Nanoparticles are solid colloid particles ranging from 1 to 1000nm in size. Nanoparticles found
to be helpful because the active drug is either dissolved or entrapped or encapsulated.
Nanoparticles of different size, shape, material, physicochemical properties can be designed. The
various classes of nanoparticles are :
Mutlifunctional:- They are coiled as Nanomedicine. e.g.. Solid lipid nanoparticles(SLN),
polymeric nanoparticles and many more. SLN consists of a solid lipid having a size range of 50-
1000nm in colloid drug delivery. Polymeric nanoparticles composed of a core material matrix
with an embedded drug having a size range of 60-200nm [45,46].
d) Nanoshells
Nanoshells consist of a special class of nano composite material which are highly functional.
Particularly nanoshells contain a dielectric material coated a thin layer of another material with
the help of specialised technique. The term nanoshell is used because of the thickness of the cell,
i.e. 1-20nm. They are highly stable, chemically inert and water soluble in nature. Nanoshells
offer advantages over conventional drug delivery and helpful in biomedical imaging and
therapeutic applications [47].
e) Quantum dots (QD)

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Particles smaller than 5nm are quickly cleared by renal filtration, this technique is used in
designing of Quantum dots. QD are semi-conductor nanocrystals having the size range of 2-
10nm and after encapsulation increases to 5-20nm. QD acts as a imaging contrast agent. This
nanostructure behaves like a magic bullet which identify to the specific organ or tissue and treat
it. The neurodegenerative disorders can be successfully treated by the help of QD. They are light
sensitive, semi-conductive particles with few nm sizes [48].
f) Superparamagnetic nanoparticles (SPIONs)
These nanoparticles contains an iron oxide core coated with an organic or inorganic material
having the size range of 5-100nm. The edge of these nanoparticles over other types is magnetic
resonance imaging (MRI) visualization. The coating material may be either inorganic (silica or
gold) and organic (phospholipids, polysaccharide and polymers). The biological activity of these
types of nanoparticle is based upon magnetisation theory which trigger the action by external
magnetic field. The potential application of SPIONs is under research, already marketed products
of SPIONs are available for diagnostic purpose [49-51].
g) Fullerenes/Nano-onions
The major component (99.9%) of fullerense is carbon, which sometimes referred as carbon
nanotubes or buckyballs, they may be a single or multi layer. The multiple layer called as nano
onion, spherical in size with multilayered core, these mutlilayer are dedicated to lubricants. The
fullerenes composed of approx. 300 carbon atoms and it holds a great promise in health care
applications. Research reveals that the therapeutic anti-oxidant property of fullerenes provides a
great support towards the treatment of CNS degenerative diseases. Fullerenes can capture
multiple electrons derived from oxygen free radicals in unoccupied orbitals. These have potential
applications in the treatment of disease where oxidative stress plays a role in the pathogenesis,
such as degenerative diseases of the central nervous system including Parkinsons disease [52].
h) Dendrimers
Dendrimers are multi-branched and mono-dispersed 3D molecules with a specific molecular
weight (MW) having a size of approximately 20nm. Dendrimers first discovered in 1978 by Fritz
Vogtle and coworkers. Dendrimers appears just like an architectural tree branching from a
central point. Dendrimers are meant for parenteral delivery directly to the tumor tissue. The
mechanism of action of dendrimers is based on two models:
1) Passive targeting via enhanced permeability retention (EPR) [55,56]
2) Active targeting by receptor mediated cell specific targeting [53,54].

CONCLUSION:
The treatment of Parkinson's disease is particularly challenging because the delivery of active
molecules to the brain is often precluded by a variety of physiological, metabolic and
biochemical obstacles that collectively comprise the Blood Brain Barrier (BBB), Blood
Cerebrospinal fluid Barrier (BCB) and Blood-Tumor Barrier (BTB). The present outlook for
patients suffering from many types of brain diseases remain poor, but recent developments in
drug delivery techniques provides reasonable hope that the formidable barriers shielding the
brain may ultimately be overcome. Drug delivery directly to the brain interstitium has recently
been markedly enhanced through the rational design of polymer-based drug delivery system.
Substantial progress will only come about, however, if continued vigorous research efforts to
develop more therapeutic and less toxic drug molecules are paralleled by the aggressive pursuit
of more effective mechanisms for delivering those drugs to brain targets.

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ACKNOWLEDGEMENT:
The authors are highly thankful to all staff members of Rayat-Bahra Institute of Pharmacy,
Education City, Hoshiarpur, Punjab, India and University School of Pharmaceutical Sciences,
Rayat-Bahra University, Mohali, Punjab, India for their constant encouragement and moral
support for preparing this article. Hereby the Authors declare no conflict of interest.

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