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2.3 Huntington’s disease (HD)
The neurodegeneration in HD is attributed to a single defective gene on chromosome 4.
HD is characterized by choreatic movem ents, dementia, behavioral, emotional and psychiat-
ric disturbances [13,85]. This is an autosomal disease that occurs due to elongation of CAG
(cytosine, adenine, and guanine) repeat; thus, onset of the disease depends upon length of
the CAG repeat [86]. Generally, there are 6e35 CAG repeats in exon 1 of the Huntingtin
gene on chromosome 4, while in HD, this repeat is more than 36 times. These can cause
the accumulation of Huntingtin protein in the neuron and further lead to neuronal death
[87,88]. Beside this, oxidative stress, glutamate-dependent excitotoxicity, metabolic and mito-
chondrial dysfunction are also responsible for the progression of HD [89]. Tetrabenazine and
its deuterated form deutetrabenazine are the only drugs approved by FDA for the treatment
of chorea, affecting about 90% of HD patients [90].
Natural compounds and herbs have antioxidant, antiinflammatory, antiapoptotic, and
neurofunctional properties that exhibit preventive or therapeutic effects in NDs including
HD. Various plants like Bacopa monnieri, Ginkgo biloba, Curcuma longa, Withania somnifera,
Panax ginseng, Centella asiatica, and phytochemicals such as flavonoids, lycopene, celastrol,
sesamol, and trehalose have shown to be effective against experimental HD. Ginsenosides,
obtained from Panax ginseng (Araliaceae) have shown beneficial effects in CNS disorders,
including NDs. They show antioxidant, anti inflammatory, and antiapoptotic activity.
TABLE 17.2 Medicinal plants with a potential to treat Parkinson’s disease (PD).
SN Biological name Family Pharmacological action References
1 Scutellaria
baicalensis
Labiatae Reduce the apoptosis, oxidative stress, mitochondrial
dysfunction, and aggregation of a-synuclein
Hu et al. [72], Li et al.
[73]
2 Erythrina velutina Fabaceae Neuroprotection and antioxidant Silva et al. [74]
3. Peganum harmala Nitrariaceae Dopaminergic neuroprotection and antioxidant Rezaei et al. [75]
4 Camellia sinensis Theaceae Dopaminergic neuroprotection and antioxidant Guo et al. [76],
Levites et al. [77]
5 Ginkgo biloba Ginkgoaceae Antioxidant, improves dopamine levels and muscle
coordination
Kim et al. [78], rojas
et al. [79]
6 Bacopa
monnieri (Brahmi)
Scrophulariaceae Reduces apoptosis, oxidative stress, mitochondrial
dysfunction and aggregation of a-synuclein
Jadiya et al. [80],
Sofia et al. [71]
7 Coffea arabica Rubiaceae Neuroprotection Chen et al. [81]
8 Juglandis semen Juglandaceae Monoamine oxidase-B inhibition, and dopaminergic
neuroprotection
Sofia et al. [71]
9 Curcuma longa Zingiberaceae Dopaminergic neuroprotection, antioxidant and
inhibits a-synuclein fibrillization
Bharath [82], van der
Merwe et al. [83]
10 Panax Ginseng Araliaceae Dopaminergic neuroprotection Hou et al. [84]
17. Impact of phytomedicines and their novel delivery systems408
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Moreover, they have exhibited neurop rotective effects against experimental HD model [91].
Flavonoids are the group of polyphenolic compounds that exhibit antioxidant, antiinflamma-
tory, and neuroprotective activity, which be helpful in several NDs, including HD [89]. Celas-
trol, is a triterpenoid isolated from Tripterygium wilfordi (thunder of God vine) and Celastrus
regelii belonging to the Celastraceae family, shows potent antioxidant and antiinflammatory
actions. Celastrol is known to prevent the production of proinflammatory cytokines, induc-
ible nitric oxide synthase and lipid peroxidation, and also shows neuroprotection against
neurotoxic HD experimental model [92]. Trehalose is a nonreducing disaccharide found in
many organisms like bacteria, yeast, fungi, insects, invertebrates, and plants. It protects the
integrity of cells by preventing protein denaturation from environmental stresses. Plethora
of research has shown that it inhibits amyloid-beta formation and aggregation, polyglut-
amine (polyQ)-mediated protein aggrega tion, decreased Huntington aggregateseinduced
toxicity and increases the autophagy activity against several proteins aggregation. Thus, it
can be useful in the HD [89,93]. Lycopene, a carotenoid found in tomato (Solanum lycopersi-
cum, family Solanaceae) has shown potent antioxidant, antiinflammatory, antiproliferative,
and neuroprotective activities, and also mitigates the various behavioral and biochemical
changes induced by experimental HD model [94]. Apart from these, a lot of phytochemicals
are available, which need to explored timely. Some important plants and their role in HD are
summarized in Table 17.3.
2.4 Amyotrophic lateral sclerosis (ALS)
ALS is a progressive motor neuron disease. It is characterized by upper and lower motor
neuronal death in the motor cortex, the brainstem, and the spinal cord. It is mainly character-
ized by restricted voluntary movement, difficulties in swallowing, speaking and breathing
due to muscle paralysis. The pathogenesis of ALS is unclear but it may be linked to family
TABLE 17.3 Medicinal plants with a potential to treat Huntington’s disease (HD).
SN Biological name Family Pharmacological action References
1 Bacopa
monnieri (Brahmi)
Scrophulariaceae Antioxidant, neuroprotective, and reduces mitochondrial
dysfunction
Choudhary
et al. [89]
2 Ginkgo biloba L. Ginkgoaceae Antioxidant, improves neurobehavioral deficits, and causes
downregulation of striatal glyceraldehyde-3-phosphate
dehydrogenase and upregulation of Bcl-xl expression
Mahdy et al.
[95]
3 Withania
somnifera
Solanaceae Antioxidants, antiinflammatory, neuroprotective, and
modulates the GABAergic neurotransmission
Kumar and
Kumar [96]
4 Curcuma longa Zingiberaceae Antioxidant, antiinflammatory, and neuroprotective Kumar et al.
[97]
5 Centella asiatica Umbelliferae Antioxidant, neuroprotective, and reduces mitochondrial
dysfunction
Shinomol
et al. [56]
2. Phytomedicines for neurodegenerative disorders (NDs): A neuropharmacological perspective 409
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history with gene mutation in chromosome 9 [98]. Presently, only few drugs like riluzole and
edaravone are approved from FDA to treat this disease symptomatically [99].
Complementary and alternative medicine including acupuncture, natural compounds,
phytomedicine, and natural therapy like yoga has been popular in the treatment of several
diseases including ALS. Plethora of research indicated that various phytomedicines and nat-
ural compounds like ginseng (Panax ginseng), Centella asiatica, Epigallocatechin gallate, garlic
(Allium sativum), curcumin, resveratrol, obovatol, wogonin, and paeonol have been suggested
as nutraceuticals for the prevention of symptoms of ALS by their antioxidant, antiinflamma-
tory, and neuroprotective action [99]. Ginseng is composed of a variety of biomolecules like
carbohydrates, proteins, amino acids, vitamins, fatty acids, and ginsenosides. It has been
shown to have protective effects against ALS by attenuating neuroinflammation and
improving motor neurons [100]. Centella asiatica increases the protection and survival time
in mice against motor neurodegeneration [99]. Epigallocatechin gallate, an active constituent
of green tea, and allicin, an active constituent of garlic, are the antioxidants and show neuro-
protection against ALS [101,102].
2.5 Spinal muscular atrophy (SMA)
SMA is a group of genetic disorders, characterized by uncontrolled movements that can be
caused by loss of skeletal muscle mass and loss of survival motor neuron (SMN) in the spinal
cord and the brain stem [103]. SMN protein is encoded by SMN1 and SMN2 genes. Defi-
ciency of these genes may lead to spinal muscular atrophy [104]. Three drugs nusinersen,
onasemnogene abeparvovec, and risdiplam are approved by FDA for treatment of SMA
[105].
Liuwei dihuang is a traditional Chinese herbal medicine that has variety of therapeutic
benefits. Its extract elevates the SMN protein level and protects motor neurons against
SMN deficiency-induced neurodegeneration, and improves the muscle strength [106]. Brucea
javanica extract and its constituent Bruceine D have the ability to correct the SMN2 spicing
defect and improve the symptom of SMA in mice [107]. Beside these, oxidative stress is
also a prime pathophysiological factor for spinal muscular atrophy. It is well established
that phytochemicals like flavonoids (rutin, quercetin, isoquercetin) have great antioxidant po-
tential, which may also be helpful in the treatment of muscular atrophy.
2.6 Spinocerebellar ataxia (SCA)
The SCAs are genetically heterogenous group of autosomal dominantly inherited progres-
sive neuronal disorders, in which the cerebellum degenerates slowly. SCAs are generally
characterized by loss of balance and coordination accompanied by slurred speech. Nearly
more than 25 distinct causes of SCAs are kno wn and most SCAs show common brainstem
dysfunction [108,109]. There is no specific drug and symptomatic treatment is recommended
for the SCAs; however, FDA accepted investigational new drug application for one molecule
CAD-1883 for its human testing in SCAs [110]. Recent studies suggested that lots of herbs
have been shown to have beneficial effects in SCAs (Table 17.4). They promote proteasome
activity, suppress the polyQ aggregation, reduce the oxidative stress, improve the motor
function, and prevent the cell death, which are dysregulated in SCAs [111].
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3. Delivery system for phytoconstituents to the CNS
The CNS is the most complicated and essential part of the body. As a result, it is critical to
protect it against any damages that may result in infection, inflammation, inappropriate acti-
vation, and even the death of brain cells [120]. The CNS is shielded by two major barriers: the
BBB and the blood-cerebrospinal fluid barrier. The BBB is defined by its specific structure and
the interplay of the brain’s acellular and cellular components. The BBB’s major role is to
ensure that there is an appropriate environment for the interaction and functioning of neu-
rons, which is critical for maintaining homeostasis, controlling efflux and influx, and protect-
ing the brain from harmful chemicals. However, the BBB, a vasculature of the CNS, operates
as a physical barrier and imposes a variety of impediments. It prevents therapeutic medicines
from reaching the CNS and makes it difficult for a wide range of pharmaceuticals, including
antibiotics, antineoplastic agents, and neuropeptides, to reach the brain via the endothelium
capillaries [121]. On the other hand, numerous ways for direct drug administration or direct
convection-enhanced delivery are employed to inject the medicines into the brain or cerebro-
spinal fluid, or via the intranasal delivery. Many alternative techni ques of medication adm in-
istration have been devised thus far (Fig. 17.2). Few of them are given in a neurologically
intrusive manner, making them unsuitable for medication administration. These are either
direct neurological injections or structural disruptions of the BBB utilizing ultrasonography.
Other approaches that have a broad spectrum and transport a wide range of medications to
TABLE 17.4 Medicinal plants with a potential to treat spinocerebellar ataxia (SCA).
SN
Biological
name Family Pharmacological action References
1 Rehmannia
glutinose
Scrophulariaceae Activates ubiquitin-proteasome system, promotes proteasome activity,
suppresses polyQ aggregation, and prevents cell death
Chen et al.
[112]
2 Pueraria
lobate
Fabaceae Activates ubiquitin-proteasome system, promotes proteasome activity,
suppresses polyQ aggregation, and prevents cell death
Chen et al.
[113]
3 Gastrodia
elata
Orchidaceae Promotes proteasome activity, prevents cell death, and improves
motor function
Chou et al.
[114]
4 Gardenia
jasminoides
Rubiaceae Modulates NRF2 signaling pathway, promotes expression of
antioxidant genes, and suppresses reactive oxygen species (ROS) levels
Chang
et al. [115]
5 Glycyrrhiza
inflata
Fabaceae Modulates Nrf2 signaling pathway, promotes expression of
antioxidant genes, suppresses ROS levels and polyQ aggregation
Chen et al.
[116]
6 Paeonia
lactiflora
Paeoniaceae Promotes expression of heat-shock proteins, suppresses polyQ
aggregation, and restores motor function
Chang
et al. [117]
7 Brassica
napus
Brassicaceae Promotes expression of antioxidant genes, suppresses ROS levels, and
improves motor function
Pohl et al.
[118]
8 Ginkgo
biloba
Ginkgoaceae Prevents Ca
2þ
influx and cell death Huang
et al. [119]
3. Delivery system for phytoconstituents to the CNS 411
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the CNS are pharmacological and physiological methods, which are both quite safe and
noninvasive.
AD, PD, and other NDs are becoming a significant public health concern, owing to
increased life expectancy and an older population. Such illnesses are notoriously difficult
to treat because they necessitate the delivery of medicines to the brain in precise doses in or-
der to elicit a pharmacological response. Despite significant breakthroughs in neuroscience
and drug delivery research, medication administration to the CNS remains a challenge
[122,123]. Efficacy concerns are thought to develop as a result of parenterally delivered mac-
romolecules failure to cross the BBB and gain access to the CNS, preventing their distribution
to brain tissues. As a result, direct nose-to-brain drug delivery (NBDD) has developed as a
potent approach for bypassing the BBB and delivering medications directly to the brain
[124]. The olfactory nerve and the trigeminal nerve are used to transport medications from
the nasal cavity to the brain in two ways: intracellular and extracellular. The intracellular
pathway’s major activity, exocytosis, plays a key role in NBDD. Molecules are transported
to the brain via intracellular transport. After con tacting the olfactory nerve, the medicines
are inhaled, then conveyed by endosome to the Golgi apparatus for processing, and ulti-
mately delivered by axonal transport to the olfactory bulb. Drugs can spread to other areas
of the brain once they reach the olfactory bulb. Extracellular pathways take the form of para-
cellular movement. Nasal epithelial cells connect to one another in a variety of ways, which
helps to restrict macromolecules from passing through the intercellular gap. These connec-
tions become permeable due to the constant turnover of neurons and basal cells. Drugs
can pass from the olfactory or respiratory epithelium to the lamina propria, through the peri-
neural space to the subarachnoid space, and finally into the brain, owing to paracellular
migration between olfactory neurons and supporting cells [125].
FIGURE 17.2 Approaches for drug delivery to the CNS. Reproduced with permission from Spandana KMA, Bhas-
karan M, Karri VR, Natarajan J. A comprehensive review of nano drug delivery system in the treatment of CNS disorders. J
Drug Deliv Sci Technol 2020; 57, 101628
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Phytochemicals such as flavonoids, cannabinoids, essential oils, and terpenes, with multi-
factorial potency, could be promising treatments for NDs. Multiple diseases have been re-
ported to be prevented by various plants and plant compounds, including AD and PD
[126,127]. Phytochemicals reduce oxidative stress and increase overall antioxidant load in
nerve cells through diverse qualities such as antioxidant and antiinflammatory agents.
They can also repair mitochondrial function, which is known to be impaired in many disor-
ders, and act as mitochondrial biogenesis enhancers, such as resveratrol. They have also been
shown to have antiapoptotic properties and to repair neuronal cell death by acting as agon ists
of neurotrophic factors, resulting in neuroprotection [99,128]. Several polyphenols, such as
quercetin, resveratrol, catechins, and genistein have been shown to improve cell-signaling
pathways linked to neuronal survival, while others serve as nonaggregators of misfolded
proteins, which are seen in practically most of NDs. Many of these compounds, however,
have poor bioavailability, low aqueous solubility, and significant hepatic first-pass meta-
bolism, resulting in rapid elimination and lower tissue and serum concentrations [2]. By
allowing direct delivery into the brain via the olfactory and trigeminal nerves, the intranasal
route developed as a viable alternative to oral or parenteral administration. The BBB is
bypassed with this method, and peripheral exposure is decreased, reducing the risk of un-
wanted effects. As a result, natural substances are viable options for treating brain illnesses,
but they frequently require loading onto nanocarrier systems in order to reach the CNS in
appropriate concentrations [129].
Various polymer- and lipid-based nanoformulations have been shown to aid in the deliv-
ery of their phytocompounds from the nose to the brain, for instance, by adhering to the ol-
factory epithelium and allowing the drug to be transported paracellularly or intracellularly,
whereas in exceptional situations, direct transport of the nanocarriers through the olfactory
and trigeminal nerve pathways [130]. According to the foregoing, nanocarriers should be
tiny (preferably less than 100 nm) in order to avoid being damaged by mucociliary clearance
and to be able to be carried via the olfactory and trigeminal nerve pathways. Simultaneously,
the nanocarriers should have mucoadhesive qualities to extend their stay in the olfactory mu-
cosa and increased drug loading to ensu re a lower dose form [131,132]. No significant evi-
dence has been produced to date confirmi ng nose-to-brain transport of intact nanocarriers,
which could be advantageous because excipient buildup in the brain could cause unwanted
side effects. A thorough examination of both lipid and polymer-based formulations and their
use in nasal delivery could help to properly assess their potential for direct nose-to-brain
transfer while also revealing their strengths and drawbacks. For effective pharmacological ac-
tion, the amount of drug given to the target location is the important endpoint. The recom-
mended dosage is determined by the amount of drug transported through the olfactory
mucosa, as well as the dynamic and strongly nonuniform transfer and distribution within
the brain. In the near future, a major focus of research will be on medication biodistribution
in the brain and its relationship to effective dose [130].
4. Nanocarriers-based delivery of phytoconstituents for NDs
Nano-based drug carriers have been developed to overcome the problem of drug penetra-
tion through the BBB without affecting or modifying the properties of the medication [133].
4. Nanocarriers-based delivery of phytoconstituents for NDs 413
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The main advantages of nanomaterials for such therapeutic objectives have been found to in-
crease absorption of drug in the CNS in a noninvasive manner, decreased biodegradability,
and lower toxicity to peripheral organs [134]. Therefore, treatment of NDs with phytochem-
icals may have significant repercussions, including improved biocompatibility, biodegrad-
ability, pharmacokinetic and therapeutic efficacy, and reduction in medication side effects
[135]. Table 17.5 summarizes a comprehensive overview of nanovehicles for the phytocon-
stituents delivery that aimed to improve bioavailability, pharmacokinetics, and pharmacody-
namics profiles.
4.1 Organic nanocarriers
4.1.1 SMEDDS
SMEDDS (self-microemulsifying drug delivery systems) are homogeneous mixtures of hy-
drophilic surfactant, co-solvents and oil that form an oil-in-water (o/w) microemulsion
quickly after gentle agitation and dilution in an aqueous medi um [171 ]. This type of super-
saturated environment has been shown to improve drug solubility at the absorption site.
The previously prop osed SMEDDS formulation of curcumin contains 20% ethanol, 60% Cre-
mophor RH40%, and 20% isopropyl myristate. Increased relative solubility and oral bioavail-
ability of SMEDDS by roughly 12%e13% was observed as compared to the curcumin
suspension [165]. Other researchers also prepared SMEDDS for curcumin [166,167].
4.1.2 Liposomes/ethosomes/niosomes/transferosomes
Nanoliposomes or liposomes, are uni- or multilamellar lipid bilayered vesicles that operate
as efficient carriers for proteins, peptides, vaccines, small compounds, tiny and long nucleic
acids, have aided in the development of medication delivery systems. Liposomes improve the
therapeutic index of new or established medications by improving drug absorption, lowering
metabolism, extending biological half-life, and lowering toxicity. Rather than the physico-
chemical qualities of the drug substance alone, the carrier’s properties play an important
role in drug dispersion [172]. Because of their huge carrying capacity, liposomes are
extremely useful as nanocarriers. Since the particles can entrap the phytochemicals and
inhibit quick removal or degradation, as well as improve penetration through the BBB, which
reduces the effective dose, they have long been utilized for the delivery of medication to the
brain [173]. Furthermore, they do not cause the unfavorable biological reactions that occur
when a foreign element is introduced into the system. Liposomes are noncarcinogenic,
nontoxic, biodegradable, nonimmunogenic, and nonthrombogenic when pretreated and
properly formulated in the brain or near the brain [174].
4.1.3 Polymeric nanoparticles/nanocapsules/nanospheres
Medication loading capacities of polymeric nanoparticles are substantial, allowing the sys-
tem to protect and sustain the included drug against degradation. As a result, drug penetra-
tion and access to the brain are becoming more likely. They can avoid macrophages due to
their stable architectures and specific characteristics, making medication transport to the
CNS easier. Nanospheres are compact polymeric matrices made by microemulsion polymer-
ization, whereas nanocap sules are made by a thin polymeric envelope encasing an oil-filled
hollow.
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TABLE 17.5 Nanocarrier-based delivery systems for phytoconstituents with a potential to treat neurodegen-
erative disorders (NDs).
Nano system Phytoconstituent Excipient Application References
Solid lipid nanoparticles Galantamine
hydrobromide
Tween 80, Pluronic F 127 Improved
bioavailability
Misra et al.
[136]
Piperine Polysorbate-80, glycerol
monostearate
Improved
solubility
Yusuf et al.
[137]
Quercetin Compritol 888 ATO, mono-, di, and
tri-glycerides of behenic acid
Improved
bioavailability
Dhawan et al.
[138]
Ferulic acid Compritol 888 ATO, EpikuronTM
200, taurocholate sodium
Improved
bioavailability
Picone et al.
[139]
()-epigallocatechin-
3-gallate
* Improved
bioavailability
Smith et al.
[140]
Curcumin Compritol 888, soy lecithin,
polysorbate 80
Improved
bioavailability
Kakkar and
Kaur [141]
Chrysin Stearic acid, lecithin, taurocholate Improved
bioavailability
Vedagiri and
thangarajan
[142]
Luteolin Glycerol monostearate, Tween-80,
phosphatidylcholine
Improved
bioavailability and
hydrophobicity
Dang et al.
[143]
Naringenin Glycerol monostearate, F68, tween
80
Improved
bioavailability
Mani et al.
[144]
Nanocapsules,
nanospheres,
nanocrystals and
polymeric nanoparticles
Chlorogenic acid Polycaprolactone, hitosan Improved stability,
bioavailability and
release kinetics
Agarwal et al.
[145]
Curcumin b-cyclodextrin, polyethylene
glycol-polylactic acid,
polyvinylpyrrolidone
Improved
bioavailability
Cheng et al.
[146]
Quercetin PLGA, polyvinyl alcohol, 5,5-
dithio-bis2-nitro benzoic acid,
acetylthiocholine iodide
Increased
therapeutic index
and reduced side
effects
Sun et al.
[147]
Ginsenoside Rg3 PLGA Improved
bioavailability
Aalinkeel
et al. [148]
Chrysin Pomegranate oil, sorbitan
monostearate poly
(ε-caprolactone), amyloid-beta
peptide (fragment 1e42)
Improved
bioavailability
Giacomeli
et al. [149]
(Continued)
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TABLE 17.5 Nanocarrier-based delivery systems for phytoconstituents with a potential to treat
neurodegenerative disorders (NDs).dcont’d
Nano system Phytoconstituent Excipient Application References
Huperzine A PLGA 5050 2A, chitosan, N-
succinimidyl 3-
maleimidopropionate
Sustained-release
effect, adhesion,
and targeting
ability
Meng et al.
[150]
Resveratrol Polysorbate 80, PLGA Improved
bioavailability
Da Rocha
Lindner et al.
[151]
Schisantherin
A
mPEGePLGA Improved oral
bioavailability
Chen et al.
[152]
Curcumin g7-PLGA, PLGA Decreased
amyloid-beta
aggregates in AD
Barbara et al.
[153], cheng
et al. [146]
Carbon nanotubes Berberine Pristine MWCNTs, tween 20,
phospholipid 90 G
Increased
efficiency
Lohan et al.
[154]
Metal nanoparticles Quercetin HAuCl4, ascorbicacid, CTAB Improved
bioavailability
Liu et al. [155]
Anthocyanin PEG, PEG-coated AuNPs Increased
efficiency
Kim et al.
[156]
Paeonia mountain
root extract
HAuCl4 Increased
efficiency
Xue et al.
[157]
Bacopa monnieri leaf
extract
H2PtCl6, NADH, DTNB Increased
efficiency
Nellore et al.
[158]
Mesoporous silica
nanoparticles
Curcumin and
chrysin
Ctab, TEOS Nose to brain
delivery
Lungare et al.
[159]
Liposomes Curcumin 1,2-Dipalmitoyl-sn-glycero-3-
phosphothioethanol (sodium, N,N-
diisopropylethy- lamine
Brain targeting Lazar et al.
[160]
a-Mangostin DSPE-PEG2000-COOH, NHS Improved
bioavailability
Chen et al.
[161
]
Curcumin Lactoferrin, olive oil Improved
solubility and
bioavailability
Bollimpelli
et al. [162]
Quercetin 2,3,5,-ri-phenyltetrazolium
chloride, lecithin, HEPES,
Halothane
Brain targeting Rivera et al.
[163]
Nanomicelles Curcumin Tween 80 Improved
bioavailability
Hagl et al.
[164]
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4.1.4 Solid lipid nanoparticles (SLNs)
The advantages of polymeric nanoparticles and lipid-based nanocarriers are combined in
SLNs [175,176]. Use of a solid matrix increases drug release control and stability, while the
presence of biocompatible lipids in the formulation renders SLNs noncytotoxic and well
tolerated by the body. The key limiting aspect in the usage of SLNs systemically is its short
half-life due to reticuloendothelial system clearance, which limits their use as a brain target-
ing device. This problem can be resolved by altering their size or modifying their surface. For
this aim, stealth SLNs can extend the duration that formulations interface with the BBB,
increasing the likelihood of the loaded active chemicals being released. Although the pro-
cesses by which SLN delivers medication to the CNS have yet to be fully understood, the
most widely accepted explanation is that SLNs alters the shape of BBB capillary tight junc-
tions, allowing the drug to enter the CNS via the paracellular pathway. SLN can promote
the brain uptake of drugs used in NDs primarily by stabilizing compounds against degrada-
tion in biological fluids or by drug-specific targeting utilizing SLN with functionalized sur-
face; this process is increasingly being used as both passive and active targeting and
enables us to enhance the selectivity The use of an SLNs formulation technique can dramat-
ically improve bioavailability for drugs in CNS that only crosses the BBB to a limited level.
Overall, SLNs evidenced their potential as drug carriers to the brain owing to their ability
to pass the BBB; they are best described by several benefits associated with their use, such
as biocompatibility of SLN ingredients with comparative lower toxicity, the potential of
controlled drug release, and potential of large-scale production. The usage of SLNs can alle-
viate difficulties including solubility, stability, toxicity, and initial hepatic metabolism, when
lipophilic/hydrophilic compounds are included. SLN is also one of the most promising drug
delivery systems due to its ability to use many administration routes [177]. Thus, one of the
TABLE 17.5 Nanocarrier-based delivery systems for phytoconstituents with a potential to treat
neurodegenerative disorders (NDs).dcont’d
Nano system Phytoconstituent Excipient Application References
Self-microemulsifying
drug delivery systems
Curcumin Cremophor RH40, isopropyl
myristate, f20% ethanol
Improved
bioavailability
Wu et al.
[165]
Curcumin Eudragit E PO, Cremophor EL,
Labrasol. Capryol 90, Labrafac PG
Improved
bioavailability
Jaisamut et al.
[166]
Curcumin Cremorphor EL, PEG 400, ethyl
oleate
Improved oral
absorption
Cui et al.
[167]
Cubosomes Curcumin Fish oil, monoolein Improved
solubility
Rakotoarisoa
et al. [168]
Piperine Poloxamer, tween 80, cremophor,
monoolein
Improved
solubility and
bioavailability
Elnaggar
et al. [169]
Hybrid nanocarrier Rutin TPGS, solutol HS 15, tween 80,
lecithin, PLGA
Improved
bioavailability
Ishak et al.
[170]
* Information not disclosed: US Provisional Patent Application #61/238,381.
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