Gauging The Role And Impact Of Drug Interactions And Repurposing in Neurodegenerative Disorders Part 7

6.5.2. Alzheimer's disease

AD represents a devastating ND leading to irreversible, progressive impairment of cognitive function, loss of memory and independence, and unusual behavior (Vargas et al., 2018). 

Our brain is an amazing and complex organ capable of processing massive amounts of information and creating amazing memories. However, sometimes we may forget important things or our memory begins to decline, which may affect our lives and work. Therefore, how to improve memory is a problem we need to think about and solve.

Neurodevelopment (ND) is an approach that contributes to the development of the human brain. As we age, our brains gradually slow down, but that doesn't mean it can't recover. Neurodevelopment can help us enhance memory and focus by exercising and training our brains.

First, a neurodevelopmental approach can enhance the brain's flexibility and adaptability. Through a variety of stimulating training, our brains can become more flexible more efficient, and faster in processing and memorizing information. For example, reading, listening to music, practicing musical instruments, and learning new languages can stimulate changes in the brain's morphology and structure, thereby enhancing memory.

Second, neural development can improve concentration. Concentration is one of the important abilities of the human brain to process and remember information. Lack of attention may impair memory, but through neurodevelopmental approaches, we can improve our ability to focus. For example, meditation, Tai Chi, yoga, and other methods can effectively improve the efficiency of concentration.

Additionally, neurodevelopment can increase cognitive thresholds. Cognitive threshold refers to the process by which we transfer information from short-term memory to long-term memory. Through neurodevelopmental approaches, we can enhance memory capabilities by training our brains to convert information into long-term memory more efficiently.

Overall, neurological development is closely related to memory. Through a neurodevelopmental approach, we can enhance our memory by increasing brain flexibility, improving concentration, and raising cognitive thresholds. In real life, we can use a variety of methods to train and exercise neural development to achieve the effect of improving memory. Let's take on the challenge of memory enhancement with a positive attitude! It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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The molecular hallmarks of AD are the extracellular deposition of amyloid-beta (Aβ) plaques and the intracellular appearance of neurofibrillary tangles consisting of hyperphosphorylated tau (Parihar and Hemnani, 2004; Kumar and Singh, 2015). 

The worldwide prevalence of AD is 4–8% and it has been estimated that the number of individuals affected by AD will reach up to 100 million by the year 2050 (Association, 2012). This shows the failure of available treatment options, the large unmet clinical needs, and thereby the requirement of disease-modifying agents for the cure of AD. 

The failure of attempts to develop superior drugs to the existing ones along with failing clinical trials for AD prompted the utilization of drug repurposing strategy in AD. These repurposed candidate drugs with high priority based on the higher level of supportive evidence can be divided into antihypertensives, antibiotics, antidiabetics, and antidepressants (Corbett et al., 2012).

6.5.2.1. Antihypertensives. Various studies have reported the relationship between hypertension and increased risk of development of AD which shows the possibility of targeting therapeutics against hypertension and thereby reducing the risk of AD (Shih et al., 2018; Carnevale et al., 2016). 

Even though there exists a relationship between hypertension and AD at the same time, it is also reported that this risk associated with hypertension does not appear to be significant in the later stages of life (Qiu et al., 2005). 

It has been proposed that antihypertensive show some kind of independent mechanisms for neuroprotection against AD along with their direct action on blood pressure. These antihypertensives commonly, angiotensin receptor blockers (ARB) and calcium channel blockers (CCB) are mainly responsible for neuroprotective effects (Corbett et al., 2012). 

ARBs show neuroprotection via directly acting on the brain or by showing peripheral effects. The central effects of ARB on the brain include blocking angiotensin II type 1 receptor (AT1R) inside the brain or blocking of AT1R outside the brain. 

Various ARBs such as losartan, telmisartan, irbesartan, olmesartan, valsartan, and candesartan have been screened to study their neuroprotective effects in AD, and in a dose-dependent manner, they have shown attenuation of central effects of angiotensin II (Culman et al., 2002; Royea and Hamel, 2020). Wang et al. screened 55 clinically approved antihypertensive drugs for their neuroprotective activity in AD with the help of primary neuronal culture generated from Tg2576 AD mouse. 

In vitro analysis showed valsartan as the only potential candidate for the attenuation of oligomerization of Aβ peptides into high molecular weight oligomeric peptides which are responsible for the deterioration of cognitive function. This attenuation of oligomerization of Aβ peptides was found to be at the 2- fold lower dose as compared to the dose used for hypertension therapy (Wang et al., 2007). 

The study was further escalated to the Tg2576 AD mice model where they administered valsartan at doses of 10 mg/kg/day to the 6-month-old old or 40 mg/kg/day to the 11.5-month-old mice. 

The study results observed that potential benefit at the dose of 40 mg/kg/day (Wang et al., 2007). The most remarkable outcome was observed in the study conducted by Danielyan et al., where they observed the protection of valsartan in the APP/PS1 transgenic mouse model of AD after its intranasal administration. 

In this study, they administered valsartan intranasally at the dose of 10 mg/kg/day to the APP/PS1 mice for 2 months which led to the 3.7-fold reduction of Aβ plaques as compared to vehicle-treated mice. 

The valsartan-treated mice also showed a reduction in serum levels of various inflammatory cytokines and showed increased serum levels of IL-10 which is responsible for the suppression of inflammation. 

Additionally, losartan also increased the expression of tyrosine hydroxylase in the striatum as well as locus coeruleus (Danielyan et al., 2010). The promising preclinical results of the ARBs as neuroprotective agents in AD have led to the clinical investigation of some of these ARBs. The compilation of completed, as well as ongoing clinical trials is summarized in Table 2. 

In view with the various in vivo and in vitro preclinical models showed promising therapeutic options of losartan and valsartan as potential candidates for neuroprotection in AD. But still, the clinical results of the various ARBs are conflicting when compared with their in vitro preclinical study results. 

Calcium channel blockers (CCBs) are another class of antihypertensive which are mainly used to control blood pressure and angina (Eisenberg et al., 2004). These drugs are found to cross the blood-brain barrier easily, thereby inducing cerebral vasodilation and causing increased blood flow to the brain (Landmark et al., 1995; Hanyu et al., 2007; Forsman et al., 1990). 

Anekonda et al. studied the effect of four L-type calcium channel blockers including diltiazem, isradipine, verapamil, and nimodipine for the investigation of its therapeutic effects in AD. 

This study was conducted on the human neuroblastoma/MC65 cell lines. All four compounds show protective effects on these cell lines against neurotoxicity induced by amyloid β protein precursor C-terminal fragment (APP-CTF). 

Isradipine was found to be more potent as compared to the other three compounds which showed protective effects against APP-CTF neurotoxicity in a nanomolar concentration (Anekonda et al., 2011). In another study by Paris et al. studied the effect of antihypertensives like dihydropyridines and non-dihydropyridines CCBs on Aβ production. 

This study was conducted on Chinese hamster ovary cells which were transfected with human APP751. The in vitro study results showed that out of all tested dihydropyridines (DHP), amlodipine, nitrendipine, and nilvadipine showed inhibition of Aβ production while others did not reduce the levels of Aβ nor increase the levels. 

In vivo, studies of nitrendipine and nilvadipine in a transgenic mouse model of AD (Tg PS1/APPsw) showed an acute reduction in brain Aβ levels along with improved clearance of Aβ across the blood-brain barrier. 

Amongst the other DHPs, nilvadipine was found to be the most effective drug which showed decreased load of Aβ in Tg APPsw (Tg2576) and Tg PS1/APPsw mice brains sideways improving learning abilities and spatial memory (Paris et al., 2011).

The promising in vitro and in vivo outcomes of some CCBs encouraged the involvement of these CCBs in human AD patients. Table 3 shows a summary of clinical trials of CCBs conducted on AD patients. 

The various studies on CCBs against AD showed the strong potential of these candidates in lowering incident AD or dementia. There exists only one clinical trial of CCBs i.e. with nilvadipine was found to be effective against AD. 

The preclinical and clinical trial studies showed the effectiveness of nitrendipine, nilvadipine, and nimodipine at the doses prescribed in the clinic. These pieces of evidence show the promising potential of CCBs for the treatment as well as prevention of AD.

6.5.2.2. Antidiabetic drugs. One of the risk factors for the development of AD is type 2 diabetes mellitus. The relationship between type 2 diabetes mellitus is quite complex and the crucial components are insulin resistance as well as inflammatory signaling pathways (Mittal and Katare, 2016). 

The available literature has revealed that various AD cases associated with type 2 diabetes mellitus showed hyperphosphorylation of tau proteins, increased concentration of cortical IL-6, and abnormal regulation in the clearance of Aβ levels when compared with nondiabetic individuals (Kulstad et al., 2006; Freude et al., 2005). 

This growing evidence showing multiple links between type 2 diabetes mellitus and AD encouraged the use of antidiabetic drugs for the treatment of AD. Various studies have reported the possible links between insulin signaling and AD development. This linking appears to be so crucial that AD is often referred to as neuroendocrine disorder or type 3 diabetes mellitus. 

The studies have revealed the impairment in insulin as well as insulin-like growth factor type I, and II expression, and signaling in the brains of AD patients (Steen et al., 2005). Insulin and insulin-like growth factors show neuroprotection and are responsible for the regulation of phosphorylation of tau proteins which are the major components of neurofibrillary tangles that appear in AD (Carro and Torres-Aleman, 2004). 

An intraventricular administration of long-acting insulin (detemir) in streptozotocin (STZ) rat model of AD has shown neuroprotective effects in AD by improving cognitive behavior and learning ability (Shingo et al., 2013). 

Several preclinical studies of intranasal insulin in AD animal models have shown promising outcomes (Chapman et al., 2018). The success of the preclinical studies led to the testing of insulin clinical trials for AD management. 

There are currently 57 clinical trial studies on the neuroprotective effects of various insulin analogs in AD patients, out of which 30 studies are completed and the remaining are ongoing (Department of Health). The commonly prescribed antidiabetic drug, metformin which is a biguanide has shown an increase in insulin sensitivity. 

However, the use of metformin in AD remains controversial due to preclinical studies that have revealed the attenuation of tau proteins by metformin (Kickstein et al., 2010; Li et al., 2012) while some of the clinical trials have observed a slight increase in the risk of AD after treatment with metformin (Imfeld et al., 2012; Moore et al., 2013).

Another class of synthetic antidiabetic drugs explored for the repurposing in AD is thiazolidinediones. The rationale for the use of these drugs in AD is due to the signs of increased expression of peroxisome proliferator-activated receptor gamma (PPARγ) in AD patients (Kitamura et al., 1999). 

The preclinical studies with these agents have shown attenuation of some of the pathological mechanisms of AD, principally reducing inflammatory gene expression, and amyloid plaque burden (Jiang et al., 2008). 

These drugs not only act on the PPARγ receptor but also have several other mechanisms of action thereby ameliorating neurodegeneration (Perez and Quintanilla, 2015). The outcome of clinical trials of rosiglitazone and pioglitazone revealed a promising outcome only for pioglitazone in mild to moderate AD patients (Cheng et al., 2016). 

The GLP-1 peptides such as exenatide and liraglutide are the further class of antidiabetic drugs that improve the release of insulin. Various studies have reported the potential of these peptides as neuroprotective agents in AD (Cheng et al., 2016). Preclinical studies have shown the neuroprotective behavior of these peptides by reducing pathological markers of AD such as Aβ plaque load, reducing activation of microglia, and improvement in memory behavior (McClean et al., 2011; Li et al., 2010b). 

The pilot study (NCT01255163) on AD patients has shown the safety and tolerability of exenatide in AD patients. 

But exenatide did not show any significant difference in comparison with placebo in clinical and cognitive measures, cortical volume, and thickness in MRI scans and serum, plasma, CSF, and plasma neuronal extracellular vesicles (EV) apart from the reduction in Aβ42 in EVs (Mullins et al., 2019). The clinical trial of liraglutide (NCT01843075) in a large AD patient population is currently ongoing at the Imperial College London.

6.5.2.3. Antibiotics. 

Recent evidence suggests a relationship between the dysbiosis of microbes in the intestine and the development of AD (Jiang et al., 2017). Increasing proof of the linkage between gut microbes and the brain led to the investigation of antibiotics in the management of AD. 

However, only certain antibiotics have shown some hope that the reduction in neuroinflammation associated with dysbiosis can provide beneficial effects in AD. The antibiotics like rifampicin (Yulug et al., 2018), minocycline (Budni et al., 2016), and rapamycin (Wang et al., 2014) in the AD animal model have shown a reduction in the Aβ levels in the brain, inflammatory cytokines, and microglia activation. 

Although these antibiotics have shown anti-inflammatory effects and improvement in the cognitive functions in AD animal models but have shown controversial results in AD (Angelucci et al., 2019).

6.5.2.4. Antidepressants. Various studies have stated that depression is a risk factor for the development of AD especially when depression is observed within two years of diagnosis of dementia (Ownby et al., 2006). 

It has been observed 30–50% as a prevalence rate of comorbidity of depression along with AD (Aboukhatwa et al., 2010). Several pathological mechanisms have been postulated which have provided the mechanistic relation between these two diseases. These include the depletion of locus coeruleus neurons and central superior raphe nucleus (Aboukhatwa et al., 2010; Zweig et al., 1988). 

In the case of depression, it leads to the release of high amounts of glucocorticoids which have adverse effects on the hippocampus and cause the development of dementia symptoms (Sapolsky, 2000). 

Depression and stress may be responsible for the reduction in neurogenesis (Warner-Schmidt and Duman, 2006). Reduction in neurogenesis leads to the development of AD-like symptoms such as acquiring and storage of information (Verret et al., 2007). 

Several studies have demonstrated the role of antidepressants for neurogenesis in the brain particularly in the two regions of the dentate gyrus of the hippocampus; the subgranular zone and subventricular zone which play a vital role in learning and memory (Abrous et al., 2005; Pechnick et al., 2011; Duman et al., 2001; Malberg et al., 2000). 

Antidepressants have been divided into various classes such as monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors. Various drugs from each class of antidepressants have shown neurogenesis in various animal models through different mechanisms of action (Kim et al., 2013). 

SSRIs represent an interesting class of antidepressants as compared to other antidepressants due to the involvement of the serotonergic system in the retention of memory as well as improvement in learning ability. The drugs under the class of SSRIs have been shown to delay the onset of AD (Mdawar et al., 2020).

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