Neural Regenerative Nanomedicine

By Mehdi Razavi

Neural Regenerative Nanomedicine presents novel, significant, experimental results relating to nanoscience and nanotechnology in neural regeneration. As current research is at the forefront of healing the nervous system, the content in the book focuses on basic, translational and clinical research in neural repair and regeneration. Chapters focus on stem cell biology to advance medical therapies for devastating disorders, the complex, delicate structures that make up the nervous system, and neurodegenerative diseases that cause progressive deterioration, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis and multiple system atrophy.

• Presents a multidisciplinary focus on all research areas surrounding the applications of nanotechnology in neural regeneration
• Provides a guide for physician and scientists, including necessary expertise for bioengineers, materials engineers, those in biomaterials and nanoengineering, stem cell biologists, and chemists
• Covers many disciplines, including bioengineering, biomaterials, tissue engineering, regenerative medicine, neural regenerative medicine, and nanomedicine

• Language: English
• Publisher: Academic Press
• Release date: Jul 21, 2020
• ISBN: 9780128204467

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Preface

Mehdi Razavi, Biionix™ (Bionic Materials, Implants & Interfaces) Cluster, Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL, United States, Department of Materials Science and Engineering, University of Central Florida, Orlando, FL, United States

Regenerative medicine focuses on using stem cell biology to advance medical therapies for devastating disorders. The complex, delicate structures that make up the nervous system—the brain, spinal cord, and peripheral nerves—are susceptible to various types of injury ranging from trauma to neurodegenerative diseases that cause progressive deterioration: Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), multiple sclerosis, and multiple system atrophy. Unfortunately, because of the complexity of the brain and spinal cord, little spontaneous regeneration, repair or healing occurs. Therefore, brain damage, paralysis from spinal cord injury and peripheral nerve damage are often permanent and incapacitating.

Patients with serious nervous system injuries or strokes often require lifelong assistance, which puts a tremendous burden on patients, their families, and society. Innovative, paradigm-shifting strategies are required to advance treatment of neurological injury. The Neural Regenerative Medicine research is at the forefront of healing the nervous system. This research is multifaceted, ranging from basic science discovery to clinical applications. Clinical trials of cell-based therapies that use pluripotent stem cells have already been started for several neurological diseases including spinal cord injury and age-related macular degeneration.

The Neural Regenerative Nanomedicine book presents novel, significant, and interdisciplinary theoretical and experimental results related to nanoscience and nanotechnology in the neural regeneration. Content includes basic, translational, and clinical research addressing neural repair and regeneration. This book will be (1) a multidisciplinary book providing broad coverage in all research areas focused on the applications of nanotechnology in neural regeneration; (2) an interesting and helpful read for physician–scientists with the expertise of neurology and regenerative medicine, bioengineers, or materials engineers with the expertise of biomaterials and nanoengineering, stem cell biologists, and chemists; (3) a reference book for different disciplines include bioengineering, biomaterials, tissue engineering, regenerative medicine, and nanomedicine.

Finally, I want to recognize and thank all contributors, the publisher, and our editorial project manager Pat Gonzalez for her excellent work.

Chapter 1

Advances and challenges toward neural regenerative medicine

Parisa Dehghani¹, Vahid Jahed² and Ali Zarrabi³, ⁴,    ¹1Department of Biotechnology, Faculty of Advanced Sciences and Technologies, University of Isfahan, Isfahan, Iran,    ²2Biomedical Engineering Division, Faculty of Chemical Engineering, Tarbiat Modares University, Tehran, Iran,    ³3Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey,    ⁴4Center of Excellence for Functional Surfaces and Interfaces (EFSUN), Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul, Turkey

Abstract

Neurodegenerative diseases such as Alzheimer, Parkinson, and Huntington diseases are injuries which have a serious negative effect on the structure and the function of the central nervous system, cognitive behavior, memory, and ability to move in patients. It is estimated that the number of people who are affected by these diseases will be increased in future decades. Unfortunately, there is no effective clinical treatment for many of the neurodegenerative disorders. Accordingly, with the advent of nanotechnology, many efforts have been made to solve the problems like crossing the blood–brain barrier and reaching the target site in the brain using novel techniques and material in field of design, synthesis, and surface modification of nanomedicine. Different types of nanomedicine have been used and studied including polymeric nanoparticles, as well as liposomes, and functionalized nanosystems. In the present chapter, we explain the challenges and advances of nanomedicine for treatment of neurodegenerative diseases after a brief description about each neurodegenerative disorders and barriers which are in front of efficient and long-term therapies.

Keywords

Neurodegenerative disease; Alzheimer diseases; Parkinson diseases; Huntington diseases; multiple sclerosis; central nervous system; peripheral nervous system

1.1 Introduction

Recently, millions of people suffer from neurodegenerative diseases like Alzheimer disease (AD), Parkinson disease (PD), multiple sclerosis (MS), Huntington disease (HD), and other brain disorders that has a collection of clinical symptoms including neuroinflammation, disrupting in selective function and destroying synapses, neurons, and aggregation of proteins which lead to behavioral and cognitional alteration in patients [1–3]. Neurodegenerative diseases have a crucial effect on health and economic of communities, but lack of information about all aspects of these diseases has led to a lack of proper clinical treatment [4,5]. Accordingly, enough information about the brain and the barriers morphology and structures are limited as the transfer of drugs and they reaching the brain tissues are necessary.

The nervous system is a network of nerve cells which control the activities and reflexes of the body and connect the body to the environment. It is divided into two general parts: central nervous system (CNS) which is consisted of the brain and spinal cord, and peripheral nervous system (PNS) that expands throughout the body. The nerve tissue is structurally composed of two types of cells: the nerve cells, which are called neurons and they receive and transmit the neural signals, and the glia cells that support the neurons and participate in activities, nutrition, and the defense processes of CNS. A neuron has three main parts: (1) a cell body or perikaryon that contains nucleus and organelles, (2) dendrites that are tree-like structures which extend away from the perikaryon to receive the signals from other neurons or environment, and (3) axons which transfer the irritation from cell body to other neurons or cells. These transmissions occur in a specific site that is called synapse where a neuron communicates with other neurons or cells [6–8].

Neurons are identified as nondividing cells and their injuries can cause a serious problem and defect for nervous system. Thus, there must be some protecting factors to support them from injuries, especially for the CNS. In this regard, the hard bony structure of the skull and spine is playing a very important role in the protection of the CNS from the external damages. Moreover, CNS has some special internal systems which act as a barrier and prevent the penetration of many substances like drugs and photogenes. These barriers put a lot of restrictions to treat the injuries and neurodegenerative disorders like AD, PD, HD, and spinal muscular atrophy [9], and entrance of photogenes such as viruses, bacteria, and fungi which cause the infection leading to inflammation of the brain or the layer of tissue which cover the CNS that called meninges [10]. In first section of this chapter we focus on different barriers in CNS, their morphology and function, and finally, different approaches to overcome these barriers will be discussed.

1.1.1 Blood–brain barrier

The brain is one of the most crucial and important organ in human and all organisms. Hence, protecting it against infection, injuries, and foreign and toxic substances are necessary because they can have an impact on neural cells which can lead to dysfunction of neurons and synapses and also disrupting transferring of neurotransmitters. Finally, all these problems affect the body control processes [11]. One of these defensive dams is blood–brain barrier (BBB).

Neural tissue protects itself from neurotoxic substances by using three barrier layers: (1) BBB which separates blood from intercellular fluid, (2) the blood–cerebrospinal fluid barrier (BCSFB) that secretes the CSF into the ventricles in collaboration with choroid plexus epithelium, and (3) arachnoid epithelium. These barriers have three fundamental and significant characteristics such as (1) continuous nonfenestrated capillaries, which allow only small molecules like ions and water to pass and prevent the transport of large molecules, drugs, pathogens, and neurotoxic molecules through the endothelial cells. (2) Existence of tight junctions (TJs) between endothelial cells. (3) Low number of transport vesicle in brain vascular endothelial cells. It should be mentioned that the subarachnoid space consists of CSF and is the place where the blood vessels pass. Injection of certain dyes into the bloodstream indicates that dyes are detectable in all tissues except the CNS [12]. This represents a kind of barrier between the blood and the CNS, which is called as BBB which is shown in Fig. 1.1.

Figure 1.1 The blood–brain barrier (BBB) which is located in central nervous system (CNS) that consist of continuous and nonfenestrated endothelial cells [13].

Apical and basolateral compartments of CNS endothelial cells make them polarized [14]. The function and integrity of BBB is related to this polarization [15]. Herein, the high resistance against hydrophilic molecules and ions is provided by TJ between lateral and apical membrane of CNS endothelial cells [16,17]. In these junctions which are complex of TJs and adherens junctions (AJs), are composed of complexes of proteins and molecules like claudins and occluding, VE-cadherin and E-cadherin as an adhesion molecule, and junctional adhesion molecules [18,19]. TJ acts as a boundary element between apical and basolateral region of plasma membrane [20] that hampers protein diffusion and controls cells transferring to the CNS from blood [21]. AJ that consists of cadherin proteins has an effect on permeability of the vessels and transmigration of neutrophils inflammation site [22,23]. Also, CNS endothelial cells show a minimum vesicle-mediated transcellular transport when compared with other cells [24]; however it is still the preferable way for transporting some macromolecules like albumin and lipoprotein in CNS [25]. The other notable point about the CNS endothelial cells is that there are no leukocyte adhesion molecules (LAMs) on their surface [26] and so the immune cells from the blood cannot enter into the CNS parenchymal. This is the cause of immune cells shortage in CNS [27].

1.1.1.1 Transport pathways across the blood–brain barrier

There are many routes for small molecules to transfer across the BBB via paracellular or transcellular pathways. Based on the properties of small molecules and under physiological condition, there are three pathways to transfer substances such as (1) paracellular diffusion which allows transportation of small hydrophilic molecules [28], (2) transcellular transportation that is specific for small lipophilic molecules [29], and (3) carrier-mediated pathway that is based on concentration gradient of molecules with aid of transporters [30].

Large molecules like peptides and proteins may penetrate and transfer via endocytosis across the BBB. Seven specific and nonspecific mechanisms exist for penetrating large molecules that are divided into passive and active pathways. In passive route, agents can cross through the TJs or lipophilic transcellular pathway that is specific for lipid substances, while in active route, large molecules can transport via the active efflux carriers, carrier-mediated transcytosis, receptor-mediated transcytosis, adsorptive-mediated transcytosis, and TJ modulation.

Carrier-mediated transcytosis is a nonspecific way for transporting glucose, amino acids, purine bases, nucleosides, and choline. Also, peptides, insulin, and transferrin could be transferred through receptor-mediated transcytosis which is a vesicular-based system and needs interaction between ligands of vesicles and cell receptors.

Based on evidences, the surface charge of CNS endothelial cells is negative. As a result, proteins with positive charge such as histone, protamine, and avidin can be absorbed and pass through BBB via adsorptive-mediated transcytosis. Active efflux carrier transportation is also crucial for cells. This route with the assistance of P-glycoprotein (P-gp), multidrug-resistant protein, multidrug resistance-associated protein, and peptide transport system-1 transporters, has this ability to participate in transfer of vinca alkaloids, cyclosporin A, and AZT [31].

1.1.1.2 Regulating the permeability of blood–brain barrier

The permeability of BBB can be regulated by inflammatory mediators, inflammatory cells including neutrophils, and also changes in the physical features of blood vessels during angiogenesis and apoptosis [32]. Inflammation is a defense response by immune system to pathogens, toxins, and damaged cells [33,34]. In inflammatory responses, groups of polypeptides such as cytokines participate. In brain inflammation the predominant polypeptide that are presented are interleukins (ILs) and tumor necrosis factors (TNFs) which are part of the family of cytokines. In this case, the hemostasis plays a key role to keep the normal activity of the brain [35]. There are many evidences and researches that demonstrate the relationship between prolonged inflammation and wide variety of neurodegenerative disease [36]. These studies showed that inflammation response can cause the BBB dysfunction which is related to neurodegenerative diseases and disorders. Based on new studies, it has been revealed that the BBB dysfunction is highly related to the release of cytokines [37–39]. Therefore, the permeability of the BBB could be increased by supplying the cytokines which would be used as biomarkers for vascular cognitive impairment [40].

1.1.1.3 Challenges of blood–brain barrier

Healthy BBB as a result of its morphology, structure, and selective permeability to certain substances, is the most important limiting factor which decreases the development of novel drugs for treatment of neurodegenerative diseases. In general, the drugs with small molecules cannot cross the BBB [41]. Also, in order to achieve the effective minimum level of drugs for brain disease, it should be prescribed with high doses of drugs. In addition, indirectly, the BBB has a negative effect on drug efficiency [1,42]. On the other hand, to overcome these problems several techniques have been designed and tested including inhibition of efflux transport, drug modification, disruption in function of BBB, and usage of nanosystem that will be introduced and explained in the following sections of the chapter.

1.1.1.4 Future of blood–brain barrier studies

For CNS therapy by novel methods a comprehensive knowledge about BBB components, function, and mechanism is necessary. The restriction function of BBB is essential for CNS but it has limited the transport of drugs like proteins, antibodies, and even small molecules to the brain [43]. In this case, a major focus should be on developing novel strategies to increase the uptake of drugs via CNS by improving the BBB permeability, or using specific and selective targets [13].

At last, by understanding and researching more and comprehensively about BBB function and its cellular pathway and molecular mechanism, innovative methods could be achieved to manipulate the BBB or therapeutic molecules in order to cross the BBB and reach the diseased sites and cells.

1.1.2 Other barriers

Ventricular and circumventricular areas are the regions of CNS that connect with more permissive barrier. Ventricle areas consist of two lateral ventricles and its third and fourth ventricles produce CSF by their capillaries and choroid plexus. Circumventricular organs (CVO) are lining the third and fourth ventricles. The CVO highly permeable capillaries are fenestrated and make possible the direct exchange from blood to brain tissue [44]. The capillaries subventricular zone which is located on the lateral walls of lateral ventricles is also having more permeability because of lack of astrocyte end feet or pericytes in this site that makes it thinner than other places [45]. Another barrier that can be seen in CNS is BCSFB. Here, the TJs between opposing surface of choroid plexus epithelial cells create this barrier which modulates the transport of molecules from fenestrated vessels of choroid plexus [46]. The blood–retina barrier (BRB) is the next barrier which has the same structure and function as BBB is located in eye and consists of two inner and outer BRBs. The BRB comprises of nonfenestrated capillaries and TJs that regulate the selective permeability of this barrier. The retinal endothelial cells cover the microvessels to maintain the vessels integrity and homeostasis in inner blood–retina barrier (iBRB). Conversely, the outer blood–retina barrier (oBRB) acts as a filter to prevent the transport of macromolecules [47]. All of these regions have the same property which is leaky BBB that can open new windows to diagnosis and treatment of neurodegenerative diseases and drug delivery systems.

1.2 Brain disorders

In general, the human nervous system controls all the activities of the body. Hence, neurodegenerative diseases are associated with symptoms that make it extremely difficult to live a patient with normal life. Our nervous system includes the brain, spinal cord, and nerves. Any disorder in the nervous system can lead to symptoms that indicate a nervous disorder. These disorders include degenerative diseases such as PD, AD, MS, and HD as well as cerebrovascular diseases such as stroke, brain tumors, and traumatic disorders of the nervous system. Moreover, some diseases are of genetic origin and others appear with the increase of age. In this section, it is attempted to introduce critical neurological disorders and then discuss current methods used for their diagnosis and treatment.

1.2.1 Neurodegenerative disease

1.2.1.1 Alzheimer disease

AD was described by Dr. Alois Alzheimer in 1907, and it is the most common neurodegenerative disorder which is characterized by dementia [48,49]. Cognitive dysfunction and memory loss are the significant symptoms of AD that may be included by confusion, poor judgment, language disturbance, and visual complaints [48]. The onset of AD can be classified into approximately 95% late-onset (>60 years) as well as 5% early onset (<60 years) [48]. In addition to age-related AD, family medical history and presence of the epsilon-4 (ε4) allele of the APOE gene increases the risk of a genetic form of the AD [50,51]. It is reported that about 25% of AD’s patients are from the family type that has more than three AD peoples in their generation and 75% is related to nonfamilial AD [48,51]. The most crucial cause of AD is mutations in the amyloid precursor protein (APP) gene, presenilin 1 or presenilin 2, which leads to the formation of insoluble plaques that result in disconnection between nerve cells, neuronal homeostasis, and kinase/phosphatase activities. Moreover, overphosphorylation of microtubule-associated protein (tau3) contributes to AD by neurofibrillary tangles (NFTs) which disrupts mitochondrial activities and axonal transport [52,53]. It was also reported that there is a link between mitochondrial dysfunction/oxidative stress and autophagy in AD [54]. Furthermore, AD is frequently influenced by intracellular α-synuclein protein Lewy bodies [48,55].

As mentioned, AD is a disease that is associated with brain amyloidosis. Therefore, aggregation prevention and removal of amyloid is the most important therapeutic target for this disease. Several pathophysiologic cascades are co-stimulators of AD that result in significant loss of cholinergic, noradrenergic, dopaminergic, and GABAergic neurons transmission in AD. Generally, there is no definitive cure or treatment for AD while for patients with moderate AD, there are medications that can help to control or reduce the progression of the symptoms [56].

Neurotransmitter-based drug therapies are being utilized using cholinesterase inhibitors and N-methyl D-aspartate (NMDA) receptor blockers. Brain biopsy studies of a patient with AD have shown a decrease in the activity of choline acetyltransferase (ChAT), which produces acetylcholine (Ach) from choline. Learning of new information ability is disrupted by the loss of cholinergic neurons, which are responsible for supplying cerebral cortical cholinergic. Animal and human studies have shown that cholinergic antagonists such as scopolamine, impair learning ability while cholinergic agonists promote the learning process. Donepezil, rivastigmine, and galantamine are drugs that control the loss of cholinergic by reducing the rate of biochemical breakdown of Ach. Generally, human-related cholinesterase included acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The role of BuChE is unclear, but levels of this enzyme and decreased levels of AChE have been observed in AD progress and their inhibition by cholinesterase inhibitors may lead to prevention of Aβ amyloid deposition [56].

L-glutamate is an excitatory neurotransmitter in the nervous system that is involved in memory and learning ability. However, glutamatergic overstimulation and excessive activity of glutamate results in the activation of many postsynaptic receptors such as NMDA receptors. Overexpression of NMDA receptors has an adverse effect on memory and dementia in AD. The administration of memantine may modulate glutamatergic function. Memantine due to rapid and voltage-dependent interactions inhibits glutamatergic excitotoxicity by noncompetitive blocking NMDA receptors [57].

The secretase enzymes represent the therapeutic target’s potential for AD therapies. The α-secretase, β-secretase, and γ-secretase are enzymes that play an essential role in the production of amyloid-β (Aβ) in the brain. The β-secretase and γ-secretase enzymes are responsible for initiating and final stage of the amyloidogenic pathway for processing APP, respectively. The inhibition of these enzymes by secretase inhibitors has shown significant results for the control of AD. In contrast, α-secretase increasing activity has reverse and nonamyloidgenic effect that leads to a decrease in the amount of APP. The α-secretase activity with the form of soluble Aβ peptides contributes to secretion of neuroprotective and synaptogenesis stimulators. It was reported that epigallocatechin gallate (EGCG), a polyphenolic flavonoid extracted from green tea leaves leads to increase in activation of α-secretase [51].

1.2.1.2 Parkinson disease

PD is a progressive chronic neurodegenerative disorder that affects 1%–2% of people over 65 years, and it is characterized by motor symptoms like bradykinesia, resting tremor, and muscle rigidity [58,59]. PD may also be associated with nonmotor signs such as dementia, insomnia, anxiety, and depression [60,61]. Age increasing, male gender, and some environmental factors involving certain pesticides, exposure to some toxic materials, and rural-living increase the risk of PD that among these, age is the most significant [59]. Besides, people with a positive family history of PD are susceptible to a genetic form of the disease approximately two- to threefold of normal ones [59]. The onset of PD can be variable like Junvile-onset (<20 years), early onset adult (20–50 years), and late-onset adult (>50 years) [62]. Regarding pathophysiology of PD, massive loss or degeneration of dopaminergic pigmented neurons located in substantia nigra pars compacta region of the midbrain is the main pathological hallmark of PD [59]. The symptoms occur after losing half of the cells due to disconnection between the motor cortex, thalamus, and basal ganglia. In addition, α-synuclein as a presynaptic neuronal protein that is encoded by the SNCA gene in the human chromosome contributes to the pathogenesis of PD [63,64]. Accumulation of α-synuclein-containing Lewy bodies due to misfolding of α-synuclein observed in the antemortem brain tissue of PD patients [65]. A high level of α-synuclein leads to cellular adverse effects like mitochondrial dysfunctionality, endoplasmic reticulum stress, and synaptic impairment [65].

At the first stage, PD can be diagnosed based on medical history, clinical signs, and neurological and physical examination. In the following, there are several dopamine-based diagnoses consist of ¹²³I-ioflupane single-photon emission computed tomography (SPECT) which is known as DaTscan for evaluation of the density of the presynaptic dopaminergic terminals in the striatum 18F-DOPAL-6-fluoro-3,4-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) scan to assess the presynaptic dopaminergic integrity and accuracy, and [¹²³I] N-ω-fluoro propyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) as a selective dopamine transporter imaging (DAT) agent are used to confirm of PD. Moreover, the standard magnetic resonance imaging (MRI) combined with diffusion tensor imaging helps in early diagnosis of PD as well as specific changes in the basal ganglia and infratentorial structures [61].

Like many neurodegenerative diseases, PD has no definitive treatment and can only be controlled with medical prescriptions. The most effective PD medication is to administer natural chemical levodopa, which is transmitted into the brain followed by conversion to dopamine. This occurs with the assistance of a natural enzyme called DOPA decarboxylase. Levodopa–carbidopa (Lodosyn) formulation with the prevention of early conversion of levodopa outside the brain, reduces common lessens side effects such as nausea. Also, Duopa in a mix gel form of carbidopa/levodopa which is infused continually to the small intestine through a tube inserted into the wall of stomach for more progressive PD [59,61].

Dopamine agonists such as FDA-approved pramipexole (Mirapex), ropinirole [Requip, rotigotine (Neupro)], and apomorphine (Apokyn, subcutaneous injectable) with dopamine-mimicking activity followed by binding to dopamine receptors are mainly used to control PD symptoms but it is not as effective as levodopa. Because of less adverse effects compared with carbidopa/levodopa, this therapy often is considered for the first medication.

There are other classes of drugs include selegiline (Eldepryl, Zelapar), rasagiline (Azilect), and safinamide (Xadago) that inhibit the brain enzyme monoamine oxidase B (MAO B) called MAO B inhibitors. This enzyme is responsible to metabolize dopamine in the brain. MAO B inhibitors may be administered alone or in combination with other methods for PD patients. Moreover, another drug called entacapone (Comtan) can also be mentioned which acts by the inhibition of the catechol O-methyltransferase (COMT) enzyme that also breaks down dopamine [59,61].

Despite nonsurgical treatments, there are a few types of surgeries available to improve the motor symptoms of PD. The most common surgery for PD is deep brain stimulation (DBS) which is used for patients with movement disorders and dystonia, and obsessive-compulsive disorder. DBS is controllable deep brain stimulation by the placement of electrodes called neurostimulator into certain areas of the brain which sends electrical signals to brain areas involved in body movement. This procedure is a bit complicated and requires sequential care as well as replacement of batteries every 3–4 years [66].

1.2.1.3 Multiple sclerosis

MS is a chronic complex neurodegenerative disease related to the CNS which has affected approximately 2.5 million patients worldwide [67]. MS symptoms consist of muscle weakness, weak reflexes, muscle spasm, difficulty in the move, miscoordination, and unbalance that disrupts the patients’ normal life [68]. Unlike PD, the MS ratio of women to men prevalence is twice and the mean of onset is 30 years old. Positive genetic factors [people with three human leukocyte antigen (HLA) alleles] and environmental conditions like ultraviolet B light (UVB) exposure, and Epstein–Barr virus (EBV) infection may also increase the risk of MS [69,70]. In description of MS pathophysiology, auto-reactive of T-cells and B-cells lymphocytes through a variety of mechanisms cross from the BBB to CNS with consequent irreversible demyelination and axonal loss [67,71]. Hence, MS is also known as an immune-mediated disease [72]. The fate of MS is neurological dysfunction along with multiple plaques formation in the gray and white matter of the brain and spinal cord. Therefore, the exact neuroanatomical location of the MS plaques by the revelation of symptoms corresponded to lesions of white matter that can help in early diagnosis of the disease [67]. Depending on the distribution of lesions in the CNS, patient-to-patient symptoms can be different completely. MRI imaging of the brain and spinal cord, and cerebrospinal fluid analysis are functional assessment of nervous system activity which are used to detect lesions related to MS disease. In the MRI method, gadolinium as an antagonist is applied to show active plaques in the nervous system as well as plaques that damage BBB [67]. About 85% of MS patients have relapsing–remitting course of disease (RRMS) and most of them are faced to risk more advanced secondary progressive MS (SPMS) after 15–20 years of manifestation. Also, ~10%–15% of MS patients present without definable relapses and it is known primary progressive MS (PPMS), which is limited to treat in this case [73]. No proven treatment for RRMS has been identified while there are several drugs through self-injectable, oral administration, and intravenous injectable on the market to control and prevent the progress of MS [68].

Self-injectable known as the first-line therapy associated with daily or weekly intramuscular or subcutaneous injection of interferon (IFN) consist of IFN β-1a (Avonex) and IFN β-1b (Betaseron). This leads to decreased relapse rates in MS patients with the reduction of BBB disruption, B- and T-cells modulation, and cytokine release regulation. In addition, injection of glatiramer acetate (GA, copaxone) is composed of a copolymer of four amino acids in the maltose/maltodextrin-binding (MBP) sequence which is diagnosed by T cell auto-reactive [67,68]. The combination of injections of IFN and GA is one of the effective treatments to reduce the progression of MS. Oral medication is easier for patients with MS. Fingolimod targets receptor destruction with binding to the sphingosine-1-phosphate receptor 1 (S1PR1). This reduces lymphocytes in the blood. Another oral drug is triflunomide (Aubiago) which is used for the treatment of RRMS. It inhibits dihydroorotate dehydrogenase activity, a key enzyme in lymphocyte biosynthesis. Natalizumab as an intravenous injection drug was approved for the first time in 2004 but it was quickly removed from the market due to the development of progressive multifocal leukoencephalopathy (PML) in some cases. After that, its modified version was released 2 years later. It is a human monoclonal antibody that prevents the migration of lymphocytes between the BBB by partially blocking CD4 T-cells. The efficiency of natalizumab to reduce the symptoms of MS is more than self-injectable IFN and GA but its use is limited because of more side effects. Hence, using of natalizumab injection is in priority if MS is not controlled by IFN and GA. In addition, other monoclonal antibodies including rituximab, obinutuzumab, and alemtuzumab are also used in the intravascular injection procedure for MS [68].

1.2.1.4 Huntington disease

HD which was found by George Huntington (1850–1916) [74], is a progressive neurodegenerative disease which is associated with various signs and symptoms including movement disorders and cognitive decline, and psychiatric symptoms such as depression, psychosis, as well as insomnia [75,76]. In addition, weight loss, skeletal-muscle wasting, and cardiac failure are common in HD patients [76]. The most common onset of HD is appeared as adult-onset while it also occurs in earlier age like before 20 years old which is called juvenile-onset HD [77]. As with most neurodegenerative diseases, positive family history has a vital role in HD [78]. The only pathologic-cause of HD is the HTT gene (located on chromosome 4p16.3) mutation which provides Huntington protein with 350 kDa molecular weight production. There is polymorphic trinucleotide repeat (CAG)n in the first exon, at the N-terminal coding region of the HTT gene through which glutamate is coded. CAG is repeated 10–35 times normally while HD patients are faced with excessive production of CAG 36 and more. This mutation leads to produce toxic elongated protein followed by accumulation in neurons with consequent neuronal dysfunction and cell death (2, 4). Hence, DNA diagnostic testing can be done to detect CAG repeats disorder in HTT on chromosome 4 [79].

HD could be diagnosed by genetic testing for finding of the defective gene, computerized tomography (CT) scan, and MRI. Clinical symptoms of the patient with HD guide doctors to immediately diagnosing the disease. Also, presymptomatic genetic testing is used for patients who have no clinical symptoms but they have a family history with HD. Indirect genetic testing, the number of CAG repeats is counted by taken DNA from a blood sample of the patient. In the advanced HD, brain imaging tests help to appear enlargement of ventricles, which are cavities filled with CSF within the brain. Although it is not specifically HD related, it can be used for a person who has early symptoms of HD. There is no cure for stopping HD but there are medical prescriptions that can help to control it. Most of the medications used to control HD have a regulatory role for neurotransmitters. For example, tetrabenazine (Xenazine) is an FDA-approved drug that is used to treat HD-associated writhing movements (Chorea) by reversible depletion of monoamines (such as dopamine, serotonin, norepinephrine, and histamine). It should be noted that xenazine is associated with common side effects like drowsiness, nausea, and restlessness. Haloperidol (Haldol) and chlorpromazine are antipsychotic drugs that have side effects such as movement suppression. However, they are used to control HD-related psychotic disorders and severe behavioral problems. Moreover, antipsychotic drugs may also increase the risk of sudden cardiac death [80,81]. Levetiracetam (Keppra, others), clonazepam (Klonopin), amantadine, and benztropine are other types of drugs used for the treatment of HD symptoms.

Indeed, there are other methods for HD treatment such as SRX246 which is a HD-specific therapy for depression and gene silencing that reduces the levels of HTT protein and is in Phase 2 clinical trial. Besides, speech therapy, physical therapy, and occupational therapy may help patients with HD to gain their lost abilities [80].

1.2.2 Other brain disorders

1.2.2.1 Brain cancer

Brain cancer, like almost all cancers, is caused by the abnormal growth of brain cells that appear as a tumor in the brain or CNS and it may also be associated with frequent headaches, double vision, and hearing and speech problems [82]. Brain cancer also sometimes invades the CNS due to cancers outside the brain [83]. Brain tumors are classified into noncancerous (benign) and cancerous (malignant) types. They are also divided into primary and secondary tumors based on their origin. Secondary tumors or metastatic tumors are tumors that may migrate to other tissues such as lung, breast, kidney, colon, and stomach [82]. About 20% of brain cancer patients are involved in brain metastasis [84]. In terms of growth rate, it is divided into two classes: high and low grade. To investigate the cause of brain cancer, like another form of cancer, the most essential reason is DNA mutations caused by viruses, inappropriate diet, bad lifestyle, and environmental factors [82].

There are invasive and noninvasive methods to diagnose brain cancer. A biopsy is an invasive procedure known as the gold standard for the diagnosis of brain cancer. A biopsy can also provide information on the type of tumor, its grade, and its potential for progression. Noninvasive techniques, like CT scans and MRI, are much safer and faster than biopsy, and they can be used for the detection of brain tumors and brain cancer progression [85].

Similar to almost all cancers, radiotherapy and chemotherapy are primary treatments for brain cancer. Also, surgery is one of the primary procedures to treat brain cancer which may be accompanied by challenges like damage to the surrounding tissues. In addition, photodynamic therapy (PDT) involves the transfer of photosensitizers (PS) such as photofrin to tumors, resulting in the production of singlet and reactive oxygen species, which ultimately leads to the apoptosis of tumor cells [85].

1.2.2.2 Spinal cord injury

Spinal cord injuries (SCI) is a bundle of nerves that is accompanied to the damage to the spinal cord or bundle of spinal nerves and spinal nerve rootlets. It is associated with a complete loss or altered motor function and sensation, and disruption of autonomic function [86]. Blunt trauma and penetrating injury leads to traumatic SCI due to the high sensitivity of spinal cord tissue and its self-repair disability; however, tumors, blood loss, and disk degeneration of the spine may also be caused to nontraumatic one [87]. Traffic, domestic, and sporting accidents as well as falls from heights are the most causes of traumatic SCI and it is more than nearly twice as prevalent in men as women [88]. Physical examination such as neck or back pain, any weakness in the arms or legs, and feeling numb in the arms and legs guide the doctors to early diagnose the SCI [89]. In addition, X-ray to detect any fracture or degenerative changes in the spine, and more advanced imaging tests such as CT scan and MRI can be used to identify this injury [89,90]. So far, no definitive cure to reverse SCI has been reported [89,91], but it is hoped that scientific progress in this field will lead to treat and control it [92].

1.2.2.3 Stroke

Stroke is a neurological deficit that is the second leading cause of death behind the ischemic heart. It is identified by vision problems, weakness in limbs, dizziness, confusion, loss of coordination, and drooping of the face on one side [93]. Westernized/sedentary lifestyles and increasing life expectancy can increase the risk of stroke [94]. Ischemic and hemorrhagic stroke are two kinds of strokes attributed to focal infarction of the brain and focal nontraumatic bleeding in the brain, respectively. Ischemic stroke or cerebral ischemia is the most common stroke in which blockage in an artery as thrombosis or embolisms causes insufficient nutrients and oxygen are delivered to cerebral hypoxia that resulted in the death of brain cells in 4–10 min, necrosis in the infarct core, and apoptosis at the periphery. Excitotoxicity, mitochondrial failure, protein misfolding, free radicals generation, and inflammation are considered as pathogens of this disease. In contrast, a hemorrhagic stroke happens by small penetrating arteries or aneurysms rupturing due to chronic hypertension, high blood pressure, and abnormal blood vessels (AVMs). This leads to bleed into the intracranial or subarachnoid space, blood accumulation over time, and puts pressure on the surrounding brain tissue that causes death or stop working the affected part of the brain completely [93,95]. Brain and neurovascular imaging including head CT and MRI scan, carotid ultrasound, cerebral angiogram, and echocardiogram [93]. Intravenous injection of recombinant tissue plasminogen activator (tPA) is an emergency treatment within after 4–5 ischemic stroke, which is helped to dissolve any blood clots. Also, a stent retriever can be used to directly remove the clots which have blocked the vessels. The basic methods to treat hemorrhagic stroke are the bleeding reduction and pressure drop in the brain. Hence, surgery is also used to repair the damaged blood vessels in this issue [96].

1.3 Novel treatment methods

Nowadays neurodegenerative disorders become pandemic in the world and most of them are incurable because of unknown steps of mechanism of these diseases and lack of efficient clinical therapies [97]. The number of clinical treatments for neurodegenerative diseases are limited and failed in field of therapy as a result of some reasons including (1) they have only this ability to slow down the diseases progress and prevent the disability but not cure them; (2) there is no commercial early diagnosis method based on biomarkers at early stage of neurodegenerative disease; and (3) the existence of BBB, which is hampering the access of drugs to the brain [4]. As a result, these common strategies lead to the disability or death of patients. Treatment of neurodegenerative disease needs novel strategies to design novel drug delivery systems to cross the barriers like BBB and provide physiological responses. For this reason, the drugs should have some characteristics to have this potential to cross the BBB including having low-molecular weight, not ionized at physiological pH, and should be lyophilized [98]. Along these difficulties and obstacles, novel strategies have been developed to increase the chance of diagnosis and treatment of neurodegenerative diseases by invasive [intrathecal delivery (BBB disruption) and intraparenchymal delivery] and noninvasive (chemical surface modifications, using prodrugs, modified drug with antibodies, or ligands) techniques [99].

1.3.1 Intranasal technique

Intranasal drug delivery has this ability to be used for local and systematic action because of its direct contact with nasal mucosa, which provides the direct entry of drug to blood circulation [100]. It is a rapid and reliable drug delivery system to CNS. This technique is widely used for delivery of variety therapeutic substances like vaccine, rhinosinusitis, seizures, migraines, sedation, and analgesia [101]. It has been confirmed that the submucosa space of the nose can provide the direct connection between olfactory and trigeminal regions which is important for targeting the drugs to the brain [102,103]. In this region because of the location of olfactory and trigeminal neural pathway on top of the nasal cavity the drugs can absorb to the brain by two peripheral olfactory and peripheral trigeminal routs [104–106]. Also there are some limitations in using this method including: using drugs with molecular weigh more than 20 kDa, increasing the hydrophilicity of the components, damaged nasal mucosa, and enzymatic degradation [107]. In order to overcome some of these limitations, nanotechnology has been used to increase the chance and efficiency of treatment of neurodegenerative diseases