Current Strategies in Treating Alzheimer and Nano-Based formulation of Curcumin as new Drug Delivery Systems against Alzheimer: A Review of in-vivo and in-vitro Evidences

Review Article

Austin J Anal Pharm Chem. 2023; 10(3): 1164.

Current Strategies in Treating Alzheimer and Nano-Based formulation of Curcumin as new Drug Delivery Systems against Alzheimer: A Review of in-vivo and in-vitro Evidences

Sharif Bakhtiar L1; Sharif Bakhtiar S2; Mohammadi Firouz Z3; Dokhai M3; Kamali P4; Rostami Z5

1Department of Nanobiotechnology, Protein Research Institute, Shahid Beheshti University, G.C. Evin, Tehran, Iran

2Department of Computer science, Computer and mathematic Institute, Shahid Beheshti University, G.C. Evin, Tehran, Iran

3Department of Genetic, Cellular and Molecular Institute, Medical Branch of Azad University, Tehran, Iran

4Department of Nanobiotechnology, Protein Research Institute, Shahid Beheshti University, GC Evin, Tehran, Iran

5Department of Reproductive Biomedicine and Stem, Rooyan Institute, Tehran, Iran

*Corresponding author: Sharif Bakhtiar L Department of Nanobiotechnology, Protein Research Institute, Shahid Beheshti University, GC Evin and Tehran, Iran. Tel: 09120621647; Fax: 02122704474 Email: l.sharifb@gmail.com

Received: November 01, 2023 Accepted: December 15, 2023 Published: December 22, 2023

Abstract

Alzheimer’s is a neurodegenerative disease that have caused many problems for the global health system.. Today, due to the increase in life expectancy and the age of the population, the number of people diagnosed with Alzheimer›s Disease (AD) is increasing [1]. AD is usually identified by cognitive dysfunction and disruption in behavioral abilities, leading to the decrease in humans productivity and function in daily life [3]. Indeed there is a growing necessity for prevention and treatment of AD [4]. Progression of AD is linked with numerous neuropathological features such as accumulation of Amyloid-ß (Aß) etc. Development of promising treatments for AD have been challenging, with no drugs approved to date. Although in trials some drugs such as Aducanumab was effective in reducing Aß plaques in the brain, clinical out-comes were not considerable [5-8]. Due to failure of multiple trials on different drugs, many researchers have focused on natural compounds [9-11]. Curcumin as one of the most popular polyphenols, have received interests due to its unique properties in targeting Aß’s aggregation [12,13]. However curcumin has disadvantages such as poor bioavailability and chemical instability [14]. To overcome these disadvantages, Nano-drug delivery systems have shown trusting results such as appropriate targeting, high bioavailability and reducing side effects [15]. In this study we have investigated novel curcumin loaded Nano particles to highlight the advantages and disadvantages of Nanoparticles in delivery of Curcumin in AD.

Keywords: Alzheimer; Curcumin; Nano; Nanoparticle; Drug; Brain

Introduction

What Cause Alzheimer?

Due to researches done on this subject, in common regions with prevalence of Dementia; Alcohol, Physical activity and Diabetes and in the next place other factors such as smoking, social engagement, anxiety, hormones, hyper/hypotension are the main cause of Dementia [16].

Alcohol

Alcohol could affect neurotransmitter in different ways which causes to harmful consequences to these pathways. Ethanol triggers inhibitory γ-aminobutyric acid (GABA) receptors, followed by the stimulation, the excitatory glutamate receptors will be suppressed. Chronic alcohol consumption can change the microbiome and causes the neuroinflammation [17]. External negative life aspects can change gut microbiome. Negative life habits such as poor die t and alcohol consumption are considered as critical risk factors for development of spordiac AD [18,19].

Physical Activity

The brain has high sensitivity to exercise, exercise in rodent models causes the neurogenesis within hippocampal and dentate gyrus’s areas, also it will enhance learning and memory abilities [20]. Evidences in this area suggested the beneficial effect of physical activity and exercise intervention on AD [21].

Diabetes

Diabetes is associated with various problems like nephropathy, neuropathy, retinopathy, diabetic foot, cognitive impairment, and many more. Age-related memory impairment is a complication having its major effect on people suffering from diabetes and Alzheimer's. As compared with normal individuals Patients suffering from diabetes are at two times higher risk of developing cognitive dysfunction [22]. In recent years Many researches have been done on correlation between Diabetes and Alzheimer, Due to the significant correlation between two diseases the term " diabetes type 3 "or "brain diabetes" have been proposed [23]. Today it is confirmed that type 2 diabetes is associated with greater brain atrophy and cognitive decline [24].

Smoking

Among other risk factors, smoking is one of the important ones that is associated with Dementia and also can be related to currency and mortality of AD [25]. Smoking may result in cerebral oxidative stress which causes the production of Amyloid beta (Aß) or tau protein pathology. In contrast never smokers had 18% lower risk of AD in compare to continuous smokers which confirms the destructive effect of smoking on cognitive decline [26].

Social Engagement

Life style intervention including social engagement has considerable effect on AD and Cognitive abilities [27]. Low social engagement may be a marker of neurocognitive vulnerability in older adults who are cognitively normal but have evidence of AD pathophysiologic change [28]. Dyer et al. [29] in a research have suggested that in patients with AD it is important to maintain the social network. in contrast poor social network in associated with experiencing serious negative symptoms.

Anxiety

AD can result into neuropsychiatric symptoms. Among AD patients, the prevalence of anxiety is about 40% and it can be a prelude of AD. Anxiety can be seen in patients with mild cognitive impairment, mild dementia, or early-onset forms of the disease and may result to clinical syndrome of Alzheimer’s disease [30]. It is reported that anxiety convey the risk of AD up to 53%. A meta-analysis done by Santebarbara et al. [31] it has been confirmed that anxiety increases the risk of AD.

Hormone

There is noticeable fact that Alzheimer’s and dementia’s prevalence are considerably different between sexes. The rate and incidence of AD is notably higher in females. Due to the findings, researchers have now begun to search about the role of sex-dependent hormones in the pathogenesis and cause of the AD [32]. Sex hormones such as estrogen changes rapidly during the female lifespan, these hormones are high during the reproductive years and it will decline naturally during the transition to menopause. Estrogen production during Women life span may increase the risk of AD [33]. Also by the research done by Quinalan et al. [34] it have been confirmed that Thyroid hormones were moderately changed in mild AD dementia with increased serum FT4, and a also there is a decrease in peripheral conversion of T4 to T3 which confirms the reduction of T3. Brain structures involved in AD development was correlated to Serum T3 levels.

Hypertension/Hypotension

Hypertension decreases the structural and functional integrity of the cerebral microcirculation and also causes microvascular rarefaction, cerebromicrovascular endothelial dysfunction and neurovascular uncoupling, which disrupts cerebral blood supply, as a conclusion hypertension considerably increases the risk of both vascular cognitive impairment and Alzheimer’s disease [35]. Among the different types of hypotension, it has been reported that the Orthostatic hypotension is common in patients with AD [36]. It is also reported that the prevalence of Orthostatic hypotension was more significant with progression of AD [37].

Amyloid Beta, Tau Protein, Mitochondrial Dysfunction, Dysregulation of Calcium Homeostasis, Proliferation of Microglia

Amyloid Beta

Aß plaques are made in neuronal endosomes by process of hydrolysis of amyloid precursor protein and this operation is done by two main enzymes: ß-secretase and γ-secretase. Under normal condition Aß has two responsibilities: profusion of activation of synapses and also reducing the synaptic excitotoxicity [38]. But under pathological condition mostly two Aß, Aß40 and Aß42 are produced by abnormal processing of ß- and γ-secretase what makes the accumulation of Aß plaques, is imbalancement of the pathway clearance and production. These small 4 kDa peptides (A4) that are mainly contained of 38 and 43 amino acids, fold into a beta-pleated sheet structures that are highly fibrillogenic. Aß42 is the most fibrillogenic and the greatest component of amyloid plaques in AD [39].

Tau Protein

Tau belongs to the family of microtubule-associated proteins MAPs that can emerge in brain cells. Alternative splicing of the human microtubule-associated protein gene MAPT leads to six tau isoforms which are contained of 352 to 451 amino acids. A normal tau isoform ratio is necessary for maintaining brain cell homeostasis and preventing neurodegenerative diseases [40]. Tau extracted from healthy adult brains is moderately phosphorylated but in contrast, detergent-insoluble NFT Tau isolated from AD brain, is unusually and highly phosphorylated [41].

Mitochondrial Dysfunction

The mitochondrion is a cellular organelle with a special structure that is formed by two membrane that is called: outer mitochondrial membrane and inner mitochondrial membrane. Inner membrane surrounds the matrix. Mitochondria is known as powerhouse of cell and contain its own DNA. During recent decades researches have suggest new hypothesis for explaining AD pathology [42].

Mitochondrial cascade hypothesis stated that mitochondrial function may affect the accumulation of Aß. Also Reactive Oxygen Species (ROS) is responsible for most of the oxidative stress in body. There are evidences that confirms Due to mitochondrial Damage in AD, the production of ROS increases. ROS is responsible for most of the oxidative stress in body [43].

Dysregulation of Calcium Homeostasis

One of the major secondary messengers is Calcium ion which is involved in cell survival, proliferation, differentiation, transcription and apoptosis. In AD, G protein coupled receptors generate secondary messengers which regulate calcium homeostasis inside cell. But in AD and pathological condition the homeostasis get damaged [44]. In normal condition, During neurotransmission, an increase in intracellular’s calcium, following membrane depolarization, transmits the signal to synapses. Therefor calcium signaling is important for neurotransmission, maintaining the synaptic plasticity and generating long term potentiation which is the basis of learning and memory [45].

Proliferation of Microglia

Microglia are the major phagocytic cells in the Central Nervous System (CNS). These cells develop from yolk sac progenitors, migrate into the developing brain, and generate a population of brain-resident phagocytes that persist for life through self-renewal [46]. Microglia cells have different responsibilities in brain as clearing apoptotic cells, releasing growth factors and nurturing neuronal metabolism and development in neurodegenerative diseases, microglia restrain extracellular protein aggregates and clear damaged neurons [47]. Still in pathological condition of AD, at first microglia was thought to be triggered by amyloid deposit. But in recent studies majority of AD risk loci are found near or in genes that in microglia are highly expressed which rises the theory of alteration in microglia ‘s genes may lead to AD [48].

Current Strategies in Treatment of Alzheimer’s Disease

As it was mentioned, AD is one of the most common neurodegenerative diseases. Despite increasing number of Alzheimer cases, there is still no effective treatment to cure or slow down the progression of the disease. Until now only six drugs have been approved by the US Food and Drug Administration (FDA): Aducanumab, Donepezil, Galantamine, Rivastigmine, Memantine, and a manufactured combination of Memantine and Donepezil. the main limitations of current AD treatment are low blood–brain barrier permeability, severe off-target of drugs, and immune abnormality [49,50].

Aducanumab

Aducanumab is a fully human IgG1 monoclonal antibody with a high affinity that acts by breaking down these ß-amyloid aggregates into smaller oligopeptides or amino acids. Aducanumab has been shown to selectively bind to parenchymal amyloid over vascular amyloid. The medicine at a high dose has the potential to slow down the cognitive decline linked with Alzheimer’s in patients with early-onset disease. However, aducanumab does not reverse memory loss [51]. Also aducanumab did not show positive effect on AD patients in comparison to placebo in control trials. The reports have shown that patients treated with Aducanumab have had several side effects such as headache, falls and diarrhea [52,53]. To conclude based on researches in this area, aducanumab can slow down a few symptoms of AD but until now there is no trusted research that shows the strong efficiency of Aducanumab on AD patients.

Donepezil

Donepezil is used to treat symptomatically AD. This drug specifically inhibits the enzyme Acetylcholinesterase (AChE). The main physiological function of AChE is to hydrolyze the neurotransmitter acetylcholine [54]. Unfortunately, due to the presence of Blood Brain Barrier (BBB), donepezil makes severe side effects after continuous administration at a high dose of 5 mg/day, such as diarrhea, bradycardia, vomiting, insomnia and anorexia. BBB in Alzheimer patients is more hindrance which makes the drug delivery to this area even more difficult [55]. Based on researches done on Donepezil, the medicine can improve the cognitive function to a certain degree. However, there is no evidence of significantly delaying the progression of the disease, and it can easily cause side effects on patients [56,57].

Galantamine

Galantamine is an alkaloid phytochemical which can inhibit the AChE activity. the advance feature of Galantamine in this field is the ability of Galantamine in crossing the blood brain barrier. galantamine can significantly reduces mortality and cognitive decline and also improved daily routine activity in mild cognitive decline patients [58]. But it is not clinically proven that galantamine can have disease modifying effect in humans. Also, galantamine does not have the ability to strongly break the vicious circle of Aß accumulation. It is suggested that early usage of galantamine has efficiency in prevention of AD but there is a strong doubt that Galantamine can be useful in treatment of AD patients [59].

Rivastigmine

Rivastigmine is one of the approved agent for the management of dementia of mild to moderate Alzheimer's disease. this medicine is the only cholinesterase inhibitor which inhibits both AChE and butyrylcholinesterase enzymes in the brain [60,61]. This molecule also has a short half-life and a hydrophilic nature, which makes it difficult for the medicine to pass through the Blood Brain Barrier (BBB) and Cerebrospinal Fluid (CSF) which results to low bioavailability of the drug [62]. Oral consumption of Rivastigmine shows different adverse effects such as nausea, vomiting, diarrhea, and cholinomimetic effects. Also, it have been reported that large plasma fluctuation happens after oral administration which is the main reason for higher incidence of cholinergic side effects [63].

Memantine

Memantine is an oral drug which functions as a noncompetitive N-methyl-D-aspartate receptor antagonist and is approved for treatment of moderate to sever AD. Unfotunatly, studies on mold to moderate and sever AD have shown that memantine has a mild but not considerable effect on clinical symptoms [64,65].

Combination of Memantine and Donepezil

In a network meta-analysis done by Gou et al [66]. it is suggested that combination of both memantine and donepezil is effective on cognitive and neuropsychiatric symptoms but in comparison to memantine alone or placebo is less acceptable [67].

Citation: Bakhtiar LS, Bakhtiar SS, Firouz ZM, Dokhai M, Kamali P, et al. Current Strategies in Treating Alzheimer and Nano-Based formulation of Curcumin as new Drug Delivery Systems against Alzheimer: A Review of in-vivo and in-vitro Evidences. Austin J Anal Pharm Chem. 2023; 10(3): 1164.