Gauging The Role And Impact Of Drug Interactions And Repurposing in Neurodegenerative Disorders Part 8

MCI is called an impairment of cognitive performance and possesses a high risk of developing Alzheimer's dementia. However, an interference leading to the delay of this progression by 5 years may reduce the chances of development of Alzheimer's dementia by 57%. 

Cognitive ability refers to people's ability to receive, process, and use information. Memory refers to people's ability to save and use information. These two abilities are inseparable and influence each other.

Cognitive impairment can negatively impact memory. Cognitive impairments include inattention, slow thinking, and decreased language understanding and expression abilities. These disorders can lead to memory loss, forgetting, confusion, disorganization, and other phenomena.

However, we should not be overly concerned about the negative impact of cognitive impairment on memory. Instead, we should focus on methods and techniques that improve cognitive abilities and memory.

First of all, in daily life, we can exercise our cognitive ability and memory by reading books, watching movies, playing games, etc. These activities can stimulate our thinking and have a good memory training effect. Secondly, we can improve cognitive abilities and memory through a healthy lifestyle. Regular exercise, maintaining a positive attitude, and getting enough sleep can all help improve cognitive abilities and memory.

Finally, we can seek professional help, such as going to the hospital to see a doctor, attending lectures, participating in training, etc. to improve cognitive ability and memory. These methods can help us overcome cognitive impairment and improve memory.

To sum up, the relationship between cognitive impairment and memory is inseparable. However, we cannot give up the pursuit of memory because of cognitive impairment. Instead, we should use various methods to improve our cognitive abilities and memory so that we can better cope with various challenges in life and work. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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The study conducted by Bartels et al. showed chronic administration of SSRI delayed the progression of MCI into Alzheimer's dementia in patients with a history of depression (Bartels et al., 2018). Recently Torrisi et al. studied the neuroprotective effect of 2 s generation antidepressants i.e. SSRIs, fluoxetine, and vortioxetine in the dose of 10 mg/kg intraperitoneally for 24 days. 

In this study, a depressive-like phenotype was induced in 2-month-old C57BL/6 mice by intracerebroventricular injection of amyloid β (1–42) (Aβ1-42) oligomers. The fluoxetine (10 mg/kg) and vortioxetine (5 mg/kg, 10 mg/kg) were administered intraperitoneally before 7 days of Aβ injection. 

The administration of Aβ oligomer leads to significant memory deficits, shortage of transforming growth factor-β1 (TGF-β1), and depressive-like phenotype along with a significant decrease in the synaptic proteins like synaptophysin and PSD95 in the hippocampus of mice brain. 

The chronic administration of fluoxetine and vortioxetine maintained the levels of TGF-β1, synaptophysin, and PSD95 in the hippocampus of the brain of the mice model. This study showed administration of fluoxetine and vortioxetine prevented cognitive defects and depressive-like phenotype in the AD mice model (Torrisi et al., 2019).

6.5.3. Multiple Sclerosis

MS is an autoimmune disorder of the central Nervous system that is mainly characterized by neural impairments such as neuroaxonal loss, demyelination, etc, and presents various phenotypes such as Primary Progressive Multiple Sclerosis (PPMS) (less common), RelapsingRemitting Multiples Sclerosis (RRMS) that marches to Secondary Progressive Multiple Sclerosis (SPMS) over time (more common) (Ransohoff et al., 2015; Lublin et al., 2014). 

The precise etiology of MS is still under investigation, but based on various emerging technologies such as operational tools in neurobiology, neuroimaging, and neuroimmunology, the occurrence of MS is believed to be multifactorial that finally causes hyperactivation of neuronal axons triggering the inflammatory immune responses leading to irreversible neuronal disability. 

Probable promoters of neurodegeneration include oxidative injury, iron accumulation, remyelination failure, and mitochondrial damage that finally leads to localized inflammation (i.e., microglial activation or B-cell dysregulation) or augmented neurodegeneration (Mahad et al., 2015; Kawachi and Lassmann, 2017). 

Achievement in the treatment can be achieved by blocking the entry of B and T lymphocytes from the peripheral blood to the CNS which invokes the inflammatory immune responses that subsequently leads to neuronal damage. 

Various anti-inflammatory drugs, immune modulators, neuroprotective agents, and chemotherapeutic drugs are under investigation for repurposing in the treatment of the relapsing and progressive type of MS.

6.5.3.1. Drugs repurposed in the treatment of RRMS. RRMS is a phenotype of MS, where patients suffer from acute intermediate relapses along with stability periods in-between that gradually march to a worsened stage of progressive MS in which motor disability reflex increases independent of relapses (Lublin et al., 2014). 

Interferon-beta (IFN-β) was among the primary approved drugs for treating RRMS that mainly had significant immunomodulatory action on inflammatory cytokines (upregulation of anti-inflammatory cytokines and downregulation of pro-inflammatory cytokines) but did not prove to have potential effects on reducing disability advancement (Weinstock-Guttman et al., 1995; Kieseier, 2011). 

Several countries like Europe, and North America had conducted randomized clinical trials to prove the effectiveness of IFN-β in treating disability but remained pointless (Kappos et al., 2001; Wolinsky et al., 2007). Other drugs such as glatiramer acetate and Mitoxantrone had only the slightest impact on treating MS and the investigation was terminated due to potential drawbacks (Wolinsky et al., 2007; Krapf et al., 2005). 

Potential efficacy in the treatment of RRMS is achieved by repurposing drugs like rituximab and ocrelizumab which are IgG1 monoclonal antibodies, that primarily target CD20 B cells leading to depletion by apoptosis, cytotoxicity, and complement-mediated cytolysis and had shown a significant reduction in the number of relapses compared to placebo. 

Based on these successful results of ORATORIO trials in the treatment of progressive MS, ocrelizumab proved to have a significant rate in reducing disability (24%) and has been approved by USFDA in the treatment of progressive MS (Bhargava et al., 2018; Montalban et al., 2017). 

BG-12 (dimethyl fumarate), initially approved for psoriasis has been repurposed as a new indication in treating RRMS due to its neuro and cytoprotective activities. 

The results confirmed that the annual relapse rate is reduced by 58% in the BG-12 group along with a decrease in MRI lesions compared to placebo at a span of 2 years (Gold et al., 2012). 

Fingolimod phosphate (FTY720) is a natural referent of sphingosine and was the first approved oral therapy in treating RRMS. It mainly interferes with lymphocyte trafficking, preventing the efflux of lymphocytes from lymphoid organs and also its infiltration into the CNS, inhibiting autoreactive interactions. It exerts immunomodulatory activity on binding to Sphingosine-1-Phosphate (S1P1) receptors (downregulating the receptors, inhibiting the synthesis of inflammatory mediators like cytokines, IL-6, 1β, TNF-α, and also upregulates the microglial production), thus enhancing neuroprotective activity (Hoffmann et al., 2015; Noda et al., 2013). 

Scientists have conducted various trials on adult male CD1 mice by collagenase VII-S (0.5 mL, 0.06 U) insertion at a dose of 0.5 μL to develop intra-cerebral hemorrhage, followed by introducing fingolimod (0.5 mg/kg) after 30 min and once daily for 2 days. 

The results supported the neuroprotective behavior of fingolimod along with decreased inflammation (Watts et al., 2018). Recent preclinical evidence revealed the potential activity of (FTY720) in the reduction of brain atopy and loss volume but showed less effectiveness in reducing disability progression which was concluded from the phase III INFORMS trial (Lublin et al., 2016.

6.5.3.2. Drugs repurposed for the treatment of progressive MS. Another category of drugs that are under investigation for treating progressive MS includes Sphingosine-1-Phosphate (SIP) Receptor Modulators such as Siponimod and fingolimod. 

Siponimod is a selective SIP-1,5 receptor modulator that can cross BBB and has direct neuroprotective effects on CNS and glial cells by decreasing recirculation and infiltration of potentially auto-active lymphocytes. 

Patients treated with this drug showed a significant reduction in relapses (80%) and also had statistical benefit in T2 lesion volume and brain MRI lesions but suffered from some adverse effects like lymphopenia, macular edema, increased liver transaminases, varicella-zoster reactivation, bradycardia, and hypertension similar to fingolimod (Gentile et al., 2016). 

Biotin is a B-complex, water-soluble vitamin essential as a co-factor for decarboxylase enzymes, and has been evaluated for its activity in progressive MS (Shirani et al., 2016). The preliminary results of a phase III trial of (MD1003) high-dose biotin in progressive MS (NCT02220933) have shown improvement in motor disability outcomes (13% of the exposed group vs 0% of the placebo group) comparatively at a dose of 100–300 mg/day). 

It was also studied that a high dose of biotin also had a positive impact on re-myelination, and brain energy production, and also helped to reduce virtual hypoxia in MS (Tourbah et al., 2015; Sedel et al., 2016). Ibudilast initially approved for ischemic stroke and asthma is investigated for safety and efficacy in Secondary and Primary Progressive MS. 

The preclinical reports revealed its neuroprotective activity and also slowed down the progression pace but had a minor impact on reducing the MRI lesions (Mizuno et al., 2004). Alpha-lipoic acid (ALA) is a natural antioxidant synthesized in the liver that mainly reduces levels of anti-inflammatory markers like IFNgamma, TGF-beta, ICAM-1, and IL-4, in patients receiving ALA compared to placebo. 

The primary outcome was a significant reduction in percent change of brain volume (0.21%) compared to placebo (0.65%) and the brain atrophy reduced by 68% (Spain et al., 2017). Simvastatin, an anti-hyperlipidemic drug was investigated for its activity in RRMS and progressive MS, revealing its cell-protective and anti-inflammatory role but did not have much impact on lesion reduction or disease progression when used as a single drug or in combination with INF-β (Bhardwaj et al., 2012; Baldassari and Fox, 2018). 

Several other drugs are currently under clinical trial investigation for its immunomodulatory, neuroprotective, and myelin repair efficacy in MS and some examples include MIS416 (NCT02228213), riluzole, amiloride and fluoxetine (NCT01910259), NeuroVax, a T-cell receptor peptide vaccine (NCT02057159), Sunphenon epigallocatechin-3-gallate, an antioxidant (NCT00799890), and Masitinib (NCT01433497). 

Apart from these drugs, a continuous search for disease-modifying strategies that promote myelin repair is in progress which mainly helps to mitigate the root cause of this disease. Imidazole antifungals and Clemastine fumarate are two groups of compounds that are intensely screened to promote remyelination (Hubler et al., 2018; Green et al., 2017). 

Enhanced objectivity and sensitivity of disability metrics in MS will further improve the ability of clinical trials to yield more sensitive assessments of drug effectiveness.

6.5.4. Huntington's disease
HD is an adult-onset ND that is mainly characterized by psychiatric disturbances, motor disabilities, and dementia (Martin and Gusella, 1986). The neuropathological changes are mainly associated with mutations encrypting the huntingtin (HTT) gene on chromosome 4 in humans (MacDonald et al., 1993). 

HTT gene mainly encodes various functional abilities such as translational, post-translational modifications, membrane-associated signaling, apoptotic prevention, vesicular, mitochondrial transport, and protein binding interactions (Rigamonti et al., 2000; Smith et al., 2009; Tian et al., 2014). 

Intense studies on the neurochemistry of this gene revealed that the HTT gene is a complex protein and it is divided into sub-domains featuring various binding capabilities. 

The N-terminal of the gene contains polyglutamine stretch encoding CAG trinucleotide sequences generally in a number 4 to 35 followed by three groups of HEAT repeats, which are essential for the protein binding and also contain sites for post-translational modifications (DiFiglia et al., 1995). 

Any sort of mutations in this expansion leads to abnormalities in the number of CAG nucleotides (>40) resulting in proteolysis causing accumulation of polyglutamine fragments in various cytoplasmic portions of the striatum, and other brain tissues that finally results in HD (DiFiglia et al., 1997). Several in vivo animal studies have been conducted to explore the activity of the HTT gene. 

A model study of mice containing only 7 CAG repeats in the HTT gene, featured cognitive defects and motor impairment whereas, mice with overexpressed HTT gene lacking polyglutamine stretch, enhanced catabolic autophagy-reducing mutations (Clabough and Zeitlin, 2006). Moreover, HTT was found to be a substrate for various proteases such as caspases, and calcium-activated proteases such as calpains. 

Caspases are cysteine-aspartate proteases that mainly cleave the HTT gene by promoting the apoptotic pathway resulting in neural impairment (Orrenius et al., 2003; Wellington et al., 2002) whereas calpains get activated due to increased intracellular Caþ2 levels (mainly due to enhanced glutamate release or by membrane depolarisation) which further results in proteolytic cleavage of HTT gene resulting in cytotoxicity (Goll et al., 2003; Gafni and Ellerby, 2002). Currently, several approaches are in use for the management of this disease but most of them are for symptomatic relief and are less approachable towards a complete cure. 

Extensive clinical studies are in line targeting various nuclear, transcriptional, and translational protein factors to achieve disease-modifying therapies and some strategies are discussed below:

6.5.4.1. Strategies promoting mutant HTT degradation. The two approaches preferred in the treatment of HD are to promote the degradation of the mutant HTT gene either by macroautophagy or by regulation of proteostasis (Bano et al., 2011). 

Autophagy is a catabolic process considered the primary destructive pathway in the pathogenesis of cancer as well as various NDs, which mainly involves the formation of autophagosome and transfers the unwanted and toxic contents to the lysosome for degradation that mainly facilitates cell stress survival, energy redemption, and cell homeostasis (Levine and Kroemer, 2008; Noda et al., 2009; Longatti and Tooze, 2009). 

Promotion of this process helps in the destruction of various aggregated toxic proteins (polyglutamine aggregates) resulting in an enhanced recovery in the condition. 

The key regulator of autophagy is the 'target of rapamycin' (TOR) which on inhibition by rapamycin, activates the negative feedback mechanism of lysosomal autophagic degradation of aggregated proteins (Kroemer et al., 2010). Use of L-type Caþ2 channel blockers such as felodipine revealed the indirect activation of autophagy mainly by inactivating calpains and by enhancing the levels of Beclin-1- and Atg proteins that promote autophagy when administered via minipumps through subcutaneous route in mice (Williams et al., 2008; Russo et al., 2011; Yousefi et al., 2006). 

Even though this strategy (autophagy) seems to be approachable, but is not very effective because of its lack of protein recognition ability (p62 or polyubiquitin) and less sequestering capacity (Martinez-Vicente et al., 2010). 

Compounds known as Autophagosome-tether compound sound (ATTEC) bind to both mutant HTT and autophagosome promoting autophagic pathway is quite amicable (Li et al., 2019). Several studies have been conducted on the effect of proteostasis in neurogenerative diseases and one such study revealed that a decrease in the level of Insulin-like growth factor-1 (IGF-1) reduces proteotoxicity and increases the life span of the nematodes and mice (Cohen et al., 2006, 2009). 

Recent findings in C. elegans exposed the presence of protein MOAG-4/SERF1-2 which on the loss of its function, reduced the mutant protein aggregation of α-synuclein or β-amyloid and huntingtin (van Ham et al., 2010). By considering all these facts, autophagy, and proteostasis have a profound role in treating HD.

6.5.4.2. Genetic approaches. Genetic approaches are considered effective disease-modifying therapies that selectively act on mutant HTT (allele-specific therapies) or may act on both mutant HTT and wild HTT (non-allele-specific therapy). 

Antisense oligonucleotides (ASO) are short, single-stranded DNA fragments containing 8–50 nucleotides and mainly bind to mRNA and arrest the translational progression of the mutant gene by promoting ribonuclease H degradation (Rossor et al., 2018). 

RG6042 (also known as HTTRX) is a non-allele-specific ASO that mainly facilitates RNA degradation on pairing with mRNA, by enhancing the levels of RNase H1, which further arrests the translational modifications of mutant and wild type of HTT gene by up to 63% when administered intrathecally followed by no dosing period of 4 months (Tabrizi et al., 2019; Kordasiewicz et al., 2012). 

The main drawback of this ASO is its non-specificity which becomes an important concern in the elimination of complete HTT gene during embryonic and post-natal stages. rs362307 and rs362331 are two allele-specific ASOs that are under clinical trials that mainly target single nucleotide polymorphism (SNPs) associated with the mutant HTT gene (Datson et al., 2017). Long-term use of ASO (non-specific) has shown adverse effects such as thrombocythemia, hepatic and renal effects, arthralgias, and so on (Liu and Zeitlin, 2017). 

RNA interference (RNAi) is a defensive mechanism where the RNA shuts its expression to protect the cells from pathogens, producing double-stranded RNA (ds RNA) which now dice the RNA into 21 fragments that are loaded into a silencing complex, where the fragments either undergo degradation or may act as the template strand for DNA (Aguiar et al., 2017; Shannon, 2020). 

This RNAi may be selective or non-selective and do not cross BBB, thus cannot be administered intrathecally. Several non-coding RNA constructs are also in the study such as small interfering RNA (siRNA), microRNA (miRNA), and short hairpin RNA, which proved to be efficacious in reducing the mutation expression on HTT (Aguiar et al., 2017). 

AMT-130, AAV5, and VY-HTT01 are miRNAs that are currently under investigation for their activity but the early results have profound efficacy in treating HD when administered via the intraparenchymal route (Barker et al., 2020). 

Monogenic disorders can be treated to a greater extent with genome editing (altering the gene sequence by inserting, deleting, or slicing of DNA sequence) strategies like zinc finger proteins or by transcription activators. Zinc finger proteins (ZFP) are specific amino acid sequences that mainly bind to the nucleases or transcription factors and modify the transcription process by cleavage of DNA. 

Engineered ZFP onto the CAG expands, successfully reduced the progression of mHTT (90%) and wHTT (15%) in stem-derived neuron fibers and also in fibroblasts upholding its selective nature (Caron et al., 2018; Zeitler et al., 2019). 

On the other hand, transcription activator-like effectors are more specific binding proteins, which on binding to mHTT sequences cause gene silencing reducing further mutagenesis (Fink et al., 2016). In most cases, genetic approaches are considered as an effective way of treating HD than other strategies. Several repurposed drugs are under investigation for the management of HD including Ceftriaxone (CFM), apomorphine, etc. 

Preclinical studies on male transgenic mice R6/2 revealed that CFM mainly regulates the expression of GLT-1, which further increases glutamate uptake, decreasing its deposition (Sari et al., 2010; Yimer et al., 2019). Subcutaneous administration of apomorphine (1 mg) had a significant recovery effect of motor dysfunction with 10–20 min and this effect is mainly due to its sedative and hypnotic effect which can be reversed by using haloperidol (2 mg) (Auffret et al., 2019). 

Copper (II) chelating drugs are under investigation for repurposing such as metformin, cyclodipeptides, and so on due to their neuroprotective effects on various ND (Lanza et al., 2018). Continuous research in genetic morphology is still in progress, which on success have a positive impact on the treatment of this rare autosomal ND shortly.

6.5.5. Batten disease

Neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease is an inherited, autosomal neuropediatric disorder mainly characterized by seizures, dementia, visual and neural impairment, and psychomotor disabilities finally resulting in premature death. 

The exact pathophysiology of this disease is still elusive, but due to the advent of advanced experimental technologies the cause for this disorder is found to be due to mutations occurring in one of the 13 genes (PPT1, TPP1, DNAJC5, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, GRN, ATP13A2, CTSF, and KCDT7) and the other hallmark of this disease is the accumulation of autofluorescent (lipofuscin or ceroid), substances in the lysosomes which mainly differentiated this disease with other similar NDs (Zeman and Dyken, 1969). 

The diagnosis of this disease can be done through disease onset, visual evaluations, brain MRI and EEG, or by examining the ultrastructure pathology of the deposits by genetic and biological tests (Kohan et al., 2009; Aldrich and Kielian, 2011). 

The most reliable approach opted in countries with advanced genetic technology is to go for enzyme activity and genetic testing whereas, in countries lacking these facilities, skin biopsy or blood examination can be an alternative approach to detect the lysosomal storage substances. 

In the case of enzyme assays, patient samples such as fibroblasts, leukocytes, chorionic villi, amniocytes, and dried blood spots are collected and mixed with specific substrates (hemoglobin-coupled synthetic substrates and Ala–Ala–Phe-coupled substrates for CTSD and TPP1) in which enzyme of interest cleaves the substrate for fluorophore formation and the absence of fluorophore confirms the presence of batten disease subtype respectively (Vines and Warburton, 1999; Sohar et al., 2000). 

Promising therapeutic approaches include gene therapy, stem cell therapies, enzyme replacement therapies, and the use of several small molecular drugs that are repurposed for this purpose.

6.5.5.1. Gene therapy. NDs are best treated with gene therapy, as the change can be at the nuclear genetic level that mainly forbids progression further and AAV-mediated gene therapy is the most promising approach. In this process, the reintroduction of lysosomal enzymes occurs via viral proteins (AAV) into the CNS that help to up-regulate the enzyme activity, decreasing the accumulation of proteins. A case study in 2018 reported that patients with mucopolysaccharidosis type IA (a lysosomal storage disorder associated with mutations in the SGSH lysosomal enzyme) when administered with a single intravenous dose of self-complementary AAV9 (scAAV9) containing human SGSH (hSGSH), crossed BBB, increased the enzyme activity and reduced the accumulation of heparin sulfate in urine and CSF thus improving the cognitive abilities (Sawamoto et al., 2018). Successful AAV-mediated gene therapy to CNS is mediated by several factors including the route of administration, dose, tropism, and immune responses to viral capsid or transgene. As AAV naturally affects humans, our immune system readily produces antibodies which may show a negative impact on the process of gene therapy thus, necessitating the continuous monitoring of the patient. Several preclinical and clinical trials are under investigation to detect the activity of AAV-mediated enzyme delivery to combat various subtypes of Batten disease. Various AAV serotypes (AAV1, AAV2, AAV5, AAV6, AAV9) are employed for this purpose either as a single vector or in combination with other vectors (Johnson et al., 2019). 

6.5.5.2. Stem cell therapy. Cell therapies are at their early stage of progress which mainly aims to restore the activity of infected parts of cells by regeneration. Repurposing this approach in the effective treatment is complex, yet amendable to provide repair to some extent. 

A study reported that a clonal neural stem cell (NSC) line, associated with lentivirus expressed a cytokine known as a ciliary neurotrophic factor (CNTF) had a positive effect on vision restoration when given intravitreally (Jankowiak et al., 2015). Human CNS-derived stem cells (HuCNS- SCs) that secreted endogenous TPP1 and PTT1 were grafted into patients with Batten disease subtypes (CLN1 and CLN2) in phase I trial, were well tolerated with no adverse effects for a longer time, and helped to recover the condition (Selden et al., 2013). 

6.5.5.3. Small molecule therapeutics/pharmacological approaches. 

Small molecule therapy is a combination of biological and pharmaceutical agents that mainly helps in monitoring the activities of the lysosome. Accumulation of proteins in lysosome may be due to improper trafficking of enzymes by endoplasmic reticulum or by Golgi complex before An ongoing phase 1 trial (NCT01586455) testing is in progress to test whether transplantation of human placental-derived stem cells aids patients with a range of diseases including NCLs.entering the lysosome for degradation (Arvan et al., 2002). 

Pharmacological chaperones are one such molecule that binds to the target proteins and monitors the trafficking to the lysosome for degradation (Fan, 2008). Read-through compounds are the entities that mainly prevent the premature termination codons that lead to nonsense mutations. 

Ataluren (also known as PTC124) is a small molecule administered orally to prevent premature termination by interacting with the ribosome and promoting the insertion of near-cognate tRNAs at the nonsense site (Roy et al., 2016) whereas, gentamicin, an aminoglycoside antibiotic binds to the aminoacyl-tRNA site of the 30S subunit, increased PPT1 and TPP1 transcript levels and enzyme activity in patients with CLN1 and CLN2 type (Sleat et al., 2001).

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