Gauging The Role And Impact Of Drug Interactions And Repurposing in Neurodegenerative Disorders Part 6

6.5.1.1. Antidiabetic drugs. 

There is increasing evidence that suggests a linkage between type 2 diabetes mellitus and the development of PD. Both diseases are age-related and share similar pathological mechanisms. 

Diabetes is a common chronic disease. If blood sugar is not treated and controlled in time, it may have a serious impact on the human body. In addition to causing various complications, diabetes can also adversely affect memory. However, we can also improve the memory of diabetic patients through scientific and effective methods, thereby improving the patient's quality of life.

After discovering memory loss in a diabetic patient, the first step is to seek medical attention promptly and undergo necessary examinations and treatments. Controlling blood sugar is a prerequisite and the most important step. By constantly testing blood sugar, understanding your blood sugar situation, and formulating a reasonable diet plan and exercise plan, you can effectively control blood sugar levels. On this basis, the impact of diabetes on memory can be prevented or reduced.

In addition, moderate mental exercise can also effectively improve the memory of diabetic patients. For example, you can play some memory training games to improve your cognitive ability and memory by exercising your brain. At the same time, you can also read more, watch movies, etc. to expand your knowledge and horizons, thereby promoting brain development and improving memory.

Good living habits are also important. Maintaining adequate sleep and reducing harmful habits such as smoking and alcohol abuse can effectively reduce the impact of diabetes on memory. In daily life, you can use some simple and easy methods to assist memory, such as taking notes, using memos, etc. These can help alleviate memory problems and improve life efficiency.

In short, although diabetes can have adverse effects on memory, we can still delay memory decline through blood sugar control, mental exercise, and good living habits. Diabetes is not a terminal disease. As long as we take it seriously, actively treat it, and take reasonable care, we can overcome memory problems and live a healthy and happy life. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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Insulin resistance is an underlying cause of the development of type 2 diabetes mellitus (Athauda and Foltynie, 2016). Insulin receptors are present in various parts of body cells including certain brain parts such as the hippocampus, basal ganglion, and substantia nigra (Unger et al., 1991). 

Various studies have shown that insulin plays an important role in the regulation of neuronal survival and growth, dopaminergic transmission, and maintenance of synapses (Gerozissis, 2003). 

Various research studies observed a connection between the development of PD and the loss of insulin signaling (Foltynie and Athauda, 2020). These clinical findings showing the role of insulin in the pathophysiology of PD suggest the use of antidiabetic drugs as a repurposed drug for the management of PD with the help of restoring the lost insulin signaling. 

Various evidence-based studies have been published in the repurposing of various antidiabetic drugs for the treatment of PD including metformin, thiazolidinediones, insulin, glucagon-like peptide-1 agonists, dipeptidyl peptidase 4 inhibitors, exenatide, etc. Patil et al. studied the effect of metformin on the 1-Methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) induced PD mice model. 

They have administered metformin 500 mg/kg orally to mice for 21 days. The study results show a strong neuroprotective effect of metformin. This neuroprotective effect was evidenced by depletion in the oxidative stress along with maintenance of tyrosine hydroxylase (TH) positive dopaminergic neurons. 

After treatment with metformin, there was an increase in locomotor and muscular activity in MPTP-induced Parkinsonian mice. Metformin also showed a significant increase in brain-derived neurotrophic factor (BDNF) which is responsible for the neurotrophic effect of metformin (Patil et al., 2014). 

Another study with metformin by Lu et al. observed the neuroprotective effect of metformin on the MPTP-induced Parkinsonian mouse model by preventing dopaminergic neuronal cell death. In this study, metformin was administered to the mice in the dose of 5 mg/mL with drinking water for 3 weeks. 

It was observed that metformin improved motor impairment along with an increase in dopamine levels in the striatum of MPTP-induced Parkinsonian mice. Metformin showed significantly improved TH positive neurons in substantial nigra pars compact of MPTP-induced parkinsonian mice. These results revealed the protective effect of metformin by preventing dopaminergic neuronal degeneration. 

Metformin also reduced (47.3%) the levels of α-Synuclein positive neuronal cells which acts as a critical parameter for the development of PD (Lu et al., 2016). Currently, Paudel et al. published a detailed review on the role of metformin on PD. 

They have also provided various ongoing preclinical and clinical studies of metformin for the management of PD. It has been observed that metformin involves the reduction of phosphorylation and aggregation of α-synuclein, attenuation of oxidative stress, prevention of mitochondrial dysfunction, modulation of autophagy by activation of AMP-kinase (AMPK) along with a reduction of neurodegeneration and neuroinflammation (Foltynie and Athauda, 2020). 

The clinical studies were performed in the Taiwanese population for evaluation of the effect of metformin along with sulfonylureas on the PD risk in type-2 diabetes mellitus patients. The study results showed metformin may reduce the risk of PD in Taiwanese patients with type-2 diabetes as compared to treatment with sulfonylureas (Wahlqvist et al., 2012). 

These published studies show the potential of metformin as a neuroprotective agent in the treatment of PD. It has been observed from the various studies that thiazolidinediones (TZD) such as pioglitazone, rosiglitazone which are the activators of peroxisome proliferator-activated receptor-γ (PPAR- γ) showed neuroprotective effects in various NDs such as AD (Landreth et al., 2008), cerebral ischemia (White and Murphy, 2010), and PD (Wang et al., 2017). 

The TZD compounds primarily act on PPAR-γ receptors which are mainly found in adipose tissues and are involved in the regulation of glucose along with lipid metabolism (Hauner, 2002). 

Recent studies showed the expression of these receptors in astrocytes and neurons (Warden et al., 2016). These receptors also play an important role in the regulation of inflammatory response and anti-inflammatory-related gene expression along with the downregulation of inflammatory cytokines by acting on microglia/macrophages (Villapol, 2018). 

Breidert et al. evaluated the role of pioglitazone on MPTP-induced Parkinson's disease in a mouse model. MPTP leads to the loss of positive neurons in disease mice but this loss has been prevented after treatment with pioglitazone in substantia nigra. MPTP-intoxicated animals showed a significant reduction in dopamine and its metabolites including dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum as compared to pioglitazone-treated mice. 

MPTP-administered mice showed increased activation of microglia which was supplemented by macrophage antigen-1 (Mac-1) and inducible nitric oxide synthase (iNOS) in substantia nigra. 

After treatment with pioglitazone, Mac-1 expression was significantly reduced (Breidert et al., 2002). In another study by Quinn et al. observed that pioglitazone has shown Monoamine oxidase-B (MAO-B) inhibitory activity in the MPTP mouse model of PD. 

After injection of MPTP in mice, there was a significant depletion of striatal dopamine, the simultaneous reduction in the TH-immunoreactivity along with neurotoxic metabolite of 1-methyl-4-- pyridinium (MPPþ). The increase in the concentration of neurotoxic metabolite, MPPþ was due to the overactivation of MAO-B in the striatum. 

After administration of pioglitazone in the dose of 20 mg/kg, twice daily by oral route showed neuroprotection in MPTP-intoxicated mice. The pioglitazone resulted in inhibition of the MAO-B enzyme responsible for the conversion of MPTP into its toxic metabolite MPPþ (Quinn et al., 2008). 

In contrast to these preclinical studies, phase-2 multicentre, double-blind, randomized clinical trials showed unfavorable outcomes for pioglitazone-treated Parkinson's patients at a dose of 15 mg/kg and 45 mg/kg (Neurol, 2015). Various studies have documented the compromised signaling of insulin in PD patients (Morris et al., 2008). The main risk factor associated with the development of PD is age. 

Normal aging also shows a decrease in peripheral insulin receptor signaling but in the case of PD, this decrease in insulin receptor signaling was found to be higher as compared to normal aging. Previous studies have observed a decrease in the mRNA levels of insulin receptors in the brain predominantly in the cortex, hypothalamus, and hippocampus. 

Fine et al. studied the effect of intranasal human insulin (Humulin) on the 6-hydroxydopamine (6-OHDA) induced PD in the rat model. They have found that intranasal insulin attenuated the motor dysfunction induced in the 6-OHDA-induced rat model at a dose of 3 IU (Fine et al., 2020). The recent pilot, single-center, double-blinded, placebo-controlled clinical trial (NCT02064166) conducted on a small group of patients showed the efficacy of intranasal insulin for the management of PD. 

The subjects received 40 IU of intranasal human insulin, Novolin R (Novo Nordisk, Denmark) once daily for four weeks before the breakfast with help of a device Via Nase (Kurve Technologies Seattle, WA). The administered dose of insulin via intranasal route was found to be safe with no significant study-related adverse effects also no changes in the serum glucose levels and no hypoglycemic events. 

The patient receiving intranasal insulin showed improvement in verbal fluency in comparison with the baseline and placebo groups. There were improvements in the disability score on the Hoehn and Yahr (HY) score which is representative of the severity of PD in terms of motor functionality and performance. 

The Unified Parkinson Disease Scale- Motor score (UPDRS) was found to be decreased for intranasal insulin as compared to the baseline. Also, intranasal insulin was found to be well-tolerated and safe (Novak et al., 2019). 

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted endogenously which is principally involved in glucose homeostasis and also involved in the activation of similar pathways as that of insulin (Drucker and Nauck, 2006). 

GLP-1 is primarily secreted in the L cells of the small intestine while a small amount of which is also secreted from the nerve endings of the having cell bodies in the nucleus of the solitary tract and caudal brainstem (Mortensen et al., 2003; Goke et al., 1995 € ). GLP-1 exerts its action via GLP-1 receptor (GLP-1R) which is a 7-transmembrane spanning G-protein coupled receptor (GPCR) (Reimann and Gribble, 2016). 

Pancreatic cells show wide expression of GLP-1R while neurons in the brain show selective expression of GLP-1R, mainly in the cerebellum, frontal cortex, hippocampus, hypothalamus, substantia nigra, and thalamus along with glial cells and astrocytes (Alvarez et al., 2005; Trapp and Cork, 2015). The important function of GLP-1 in the brain is to reduce oxidative stress, stimulating neuronal growth as well as proliferation along with inhibition of apoptosis and modulation of inflammatory pathways (Holscher, 2012 € ). 

The downstream signaling of GLP-1 through its receptor is mainly responsible for cellular survival along with the inhibition of proapoptotic pathways which was found to be activated in the PD (Li et al., 2010a; Drucker, 2003). 

This endogenously secreted GLP-1 was found to be actively cleaved and degraded by a circulating enzyme known as dipeptidyl peptidase IV (DPP-IV) into an inactive metabolite that does not show any activity against GLP-1R (Deacon, 2004). This degradation of GLP-1 led to the discovery of an analog of GLP-1 which is a naturally occurring peptide called exendin-4 (Holz and Chepurny, 2003). 

This was recovered from the saliva of a venomous lizard known as the Gila monster (Heloderma suspectum) (Parkes et al., 2013). This natural analog of GLP-1 was found to be resistant to the circulating DDP-IV. Since then, the synthetic analogs based on the exendin-4 were developed namely, exenatide, dulaglutide, liraglutide, lixisenatide and which are licensed for the management of type-2 diabetes mellitus (Nielsen, 2005; Garber, 2012). As discussed earlier one of the major unmet clinical needs of the PD is the unavailability of disease-modifying therapeutic options. 

Disease-modifying therapeutics are nothing but therapeutic options that have the potential to reduce the neurodegeneration rate or are responsible for halting the disease process (Kalia et al., 2015). 

The GLP-1 analogs such as exenatide were found to be a potential disease-modifying therapeutic for the management of PD (Lang and Espay, 2018). Exenatide along with other GLP-1 agonists has shown promising therapeutic efficacy against various animal models of PD including 6- OHDA and lipopolysaccharide (LPS) (Li et al., 2009), 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) (Harkavyi et al., 2008), etc. 

These studies have revealed that after the administration of neurotoxins, there was a steady loss of dopaminergic neurons that led to the development of PD in the animals. This was further confirmed by behavioral, rotarod, pol test along with apomorphine challenge test, etc. The reversal of PD symptoms was observed significantly after the administration of GLP-1 agonists. 

The other analogs of GLP-1which were previously approved for type-2 diabetes mellitus have also been studied for the management of PD including liraglutide, lixisenatide (Liu et al., 2015), and semaglutide (Zhang et al., 2018b), etc. 

These GLP-1 agonists are under clinical trials for the management of PD. Exenatide has completed phase 2 of the randomized, double-blinded placebo-controlled clinical trial (NCT01971242). 

This study was conducted on 62 randomly assigned patients where 32 patients received exenatide (Bydureon) in the dose of 2 mg subcutaneously once a week while 30 patients were assigned a placebo. The primary outcome of this study was the difference in the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) motor subscale (part 3). 

Exenatide was found to be well tolerated in PD patients. The off-medication group of patients receiving exenatide showed improvement in the MDS-UPDRS score by 1.0 points while the placebo group showed worsening of the MDS-UPDRS score by 2.1 points after the 60 weeks of treatment. 

Apart from the MDS-UPDRS score, there were no statistically significant differences in the other parameters were observed between exenatide-treated and placebo groups (Athauda et al., 2017).

6.5.1.2. Iron targeting agents. 

Various reports suggest that iron leads to the induction of oxidation of dopamine which in turn causes the progression of PD due to the accumulation of dopamine-derived quinones along with reactive hydroxyl radicals (Jiang et al., 2013; El-Ayaan et al., 1997). 

Accumulation of iron in the SNpc may precede the beginning of the clinical symptoms of PD. This accumulation and deposition are mainly associated with aging (Mochizuki and Yasuda, 2012). Treatments that aim to reduce iron content are promising approaches for slowing disease progression in PD (Mounsey and Teismann, 2012). 

There is the number of chemical iron chelators including deferral (Jiang et al., 2006), deferiprone (Sun et al., 2018), apomorphine (Stacy and Silver, 2008), hydroxyquinolines (Mena et al., 2015) have already been approved for various disease conditions and also shown promising therapeutic options for the PD (Jiang et al., 2006; Kaur et al., 2003; Moreau et al., 2018). 

The randomized double-blinded, placebo-controlled clinical trial of deferiprone in PD patients evaluated the safety of the drug, changes of iron content in the brain with the help of Magnetic resonance imaging (MRI), and the clinical status of PD concerning UPDRS scores. The study results showed that deferiprone was safe and might reduce the iron content in specific regions of the brain (Martin-Bastida et al., 2017). 

Iron chelation is associated with several unsolved issues including a dose of the drug, lack of a specific target along a selection of disease stages for the enrolment of a patient. There also remains a question regarding the efficacy of iron chelation therapy on PD disease modification (Elkouzi et al., 2019).

6.5.1.3. Mitochondrial stress pathway targeting agents. 

Mitochondria represents the vital organelle of a cell playing an important role in energy metabolism along with redox homeostasis (Yin et al., 2014). It has been reported that the involvement of excessive degradation of mitochondria in the pathophysiology of sporadic as well as familial PD (Twig and Shirihai, 2011). The drugs targeting mitochondrial stress pathways are promising therapeutic options in PD. 

Inosine is a purine nucleoside that has shown a promising role as a neuroprotective agent. It acts as an anti-inflammatory agent thereby providing protective action in neurons. Inosine metabolite, urate acts as an antioxidant, and individuals with elevated levels of urate in serum have shown a decreased risk of PD. 

In various animal models of PD such as MPTP (Nishikawa et al., 2017), rotenone (El-Shamarka et al., 2020), inosine has shown a promising anti-parkinsonian effect. These results have provoked the commencement of clinical studies of the inosine for the management of PD. In Sure-PD, a dose-ranging, randomized, double-blind, placebo-controlled trial (NCT00833690) of inosine, safety, tolerability, and urate elevating capacity of inosine was evaluated in an early stage of PD patients. 

A total of 164 patients participated, out of which 75 patients met the eligibility criteria. The patients were randomized into 1:1:1 ratio groups based on placebo, inosine with a dose titrated to elevate mild levels of urate in the serum (up to 6.1–7.0 mg/dL), and inosine with a dose titrated to elevate the moderate levels of urate in the serum (up to 7.1–8.0 mg/dL) for 25 months. 

The inosine therapy was found to be safe and well-tolerated in PD patients, though three patients showed symptomatic nephrolithiasis. Urate levels in serum and cerebrospinal fluid were found to be increased with an increase in the dose of inosine (Schwarzschild et al., 2014). Another non-randomized, single-center, open-label clinical trial of inosine was conducted in Japan. 

In this trial, they enrolled 10 Asian PD patients and the study was aimed at assessing the safety and efficacy of inosine. The dose of inosine was adjusted to maintain the serum urate levels in the range of 6.0–8.0 mg/dL. 

The inosine was found to be safe and well-tolerated in this study and the patients did not show any problematic adverse effects. In this study, the disease progression was not observed in all the participating patients. These study results were found to be satisfactory but the only limitation was found to be a small patient population targeting a specific region (Iwaki et al., 2017). 

Phase 3 (SURE-PD 3), a multicenter, randomized, double-blind, placebo-controlled trial (NCT02642393) was conducted on 298 PD patients and completed recently. In this study, the capsules containing 500 mg of inosine were given orally to the treatment groups while lactose-containing capsules were given to the placebo group, three times a day for 24 months. 

The dose of inosine was further titrated to achieve serum urate levels in the range of 7.1–8.0 mg/dL. The primary outcome of the study was the estimation of the rate of change in MDS-UPDRS I-III total score over 24 months after initiation of dopaminergic therapy.

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