Abstract
Curcumin is widely used in spices in Asia. It has been widely explored for various diseases as therapeutic agent. Alzheimer’s disease (AD) is a neurodegenerative disease associated with dementia and cognitive disabilities. With the progression of disease, various changes appear in the brain cells that greatly affect the daily routine of the patient including sleep-wake disturbances. In the last few decades, extensive research has been carried out on this disease suggesting the development of non-steroidal anti-inflammatory drugs for its treatment. Since long, turmeric has been used in Asian countries as a home remedy for treating various ailments. Curcumin is an active ingredient isolated from the turmeric plant and is composed of curcuminoids. Because of its anti-inflammatory, antioxidant, anti-apoptotic and neuroprotective properties, curcumin can be safely administered to stop the progression of dementia and can be used for the development of such drugs that can reverse the neurotic damage caused by AD. This review article provides a comprehensive overview on the research carried out for AD using curcumin as active model drug.
Introduction
Since the emergence of human civilization, plants and herbs have been used for treating various infections and diseases. This trend is higher even today in most of the developing countries. Recent research shows that around 80 percent of individuals in Pakistan, Bangladesh and India rely on plants and their products for their primary health-care needs. Among all the herbs and plants used in daily routine, turmeric a rhizomatous plant from family Zingiberaceae, is very important, renounced and well known traditional plant [1–3]. This plant is a very rich source of Curcumin which is a beta-diketone that is methane in which two of the hydrogen’s are substituted by feruloyl groups. Curcumin, a bio-product has widely been explored for its health benefits and pharmacological studies. It is currently under clinical trials for a vast range of diseases such as cancers including lungs cancer, breast cancer, prostate cancer, pancreatic and colon cancer, multiple myeloma, multiple sclerosis, myelodysplastic syndromes, psoriasis and most importantly Alzheimer’s disease (AD) [4–7].
AD is a progressive degenerative disease mainly affecting the brain cells resulting in intellectual decline usually beginning with the inability to recall recent memories. It is the most prevalent cause of dementia triggering a continuous decline in thinking and social & behavioral competence of the individual, disrupting the person’s ability to work individually [8, 9]. Major risk factor contributing to the development of AD is family history as recent twin and family studies suggest that genetic factors are responsible for about 80 percent of the cases [10]. Other factors contributing towards the progression of AD are history of hypertension, cerebrovascular diseases, smoking, type II diabetes, cardiovascular diseases, blood plasma lipid levels, metabolic diseases, obesity and traumatic brain injuries. All these diseases contribute in one way or another towards the progression of dementia [8, 11].
Alzheimer disease and sleep disorders: An overview
Sleep is necessary for the physiological functions of central nervous system (CNS), specifically for those portions of the brain that are related to memory functions and strengthening. Although sleep is a genetically controlled phenomenon certain environmental factors have a great impact on the duration, intensity, quality and structure of sleep that take place during the lifetime of an individual [12, 13].
Every individual requires an average of seven hours sleep per night, however, with increase in the age, changes in sleep patterns are observed in some individuals. A well balanced sleep at night and day time naps are considered to have enhancing and stabilizing effects on memory processes, learning skills and abilities, procedural memories and memories related to conscious events [14]. Patients with sleep disorders may experience depression, anxiety decreased quality of life generally while aged patients may face vision difficulties, problem with maintaining the balance of the body and cognitive dysfunction such as impaired memory [15]. In previous studies, a close association has been observed between sleep and various disorders of the CNS such as headache, parkinson’s diseases, epilepsy, multiple sclerosis, cerebrovascular diseases and neurodegenerative diseases such as AD [12].
AD is a progressive neurodegenerative disease resulting in behavioral changes and gradual decline of cognitive functions. Histological changes observed in the CNS during AD are neurofibril tangles, senile plaques and considerable neuronal loss that is caused by two types of proteins i.e. amyloid-β-protein (Aβ) and tau proteins. Amyloid-β-protein is the basic component of plaques while tau plays its role in neurofibril tangles. In AD, huge amount of fibrillary amyloid-β-protein are accumulated in brain resulting in loss of synapses and deterioration of neuronal functions [16].
Among the various risk factors such as obesity, neural diseases, diabetes, heart problems that contribute to the development of AD, sleep disorder also plays a pivotal role in the progression of the disease [12, 17]. According to various studies, around 40 percent of Alzheimer’s patients experience sleep disturbances and night time behavioral changes such as difficulty in falling asleep, increased sleep fragmentation, wandering at night, waking up too early in the morning, night and day confusion, sleepiness resulting in recurrent day time naps, extended time period of intra sleep-wakefulness and nightmares [18–22].
These sleep problems in Alzheimer’s patients are thought to be multifactorial including the deterioration of neuronal pathways that regulate the normal sleep-wake patterns and sleep framework of an individual, along with some other somatic and psychological problems that play a major role in sleep disturbances. As a result cognitive and sleep dependent memory processes of the patient are greatly affected [23, 24]. These sleep disturbances can be used as an important diagnostic criteria for early detection of the disease as these problems tend to intensify and worsen with time [19].
Chemistry of curcumin
Curcumin is an essential active element extracted from the rhizomes of turmeric plant (Curcuma longa L.) that is a common member of family Zingiberaceae [25–27]. Curcuma longa L is a perennial plant having orange pulpy tuberous rhizomes that is predominantly cultivated in Asian countries but is commonly used around the world as condiments & as medicine and is known by different names in different languages [3, 28]. It is used as spice and food color in Asian house-hold, for making certain cosmetic products and as medicines for various ailments. Its paste is applied to prevent scabbing in chicken pox. Different preparations of turmeric are applied to wounds and bruises to avoid irritation [29]. Due to its bright orange color, it is also used as fabric dye and as coloring agent in food industry under the name Natural Yellow 3 and E100 [30–33].
Curcumin (shown in Fig. 1) is also known as diferuloyl methane is a symmetric polyphenolic diketone molecule with a molecular weight and melting point of 368.4 AMU of 183°C respectively [33–35]. Its IUPAC name is (1E, 6E)-1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione with chemical formula of C21H20O6 [25, 36–39]. Commercial grade curcumin is composed of curcuminoids i.e. bis desmethoxycurcumin (MW 308; normally less than 5%) and desmethoxycurcumin (MW 338; normally 10–20%) [40, 41]. It is perfectly soluble in organic solvents such as ethanol, acetone, methanol and dimethylsulphoxide while insoluble in aqueous solvents. It is stable at acidic pH and its degradation is considerably slow which is less than 20 percent at 1 hour but unstable at basic and neutral pH and degrades to feruloylmethane and ferulic acid within 30 minutes [3, 42].
Chemical structure of Curcumin.
Curcumin has been used for treating various ailments in Asian households since very long. Its usage has been increased with time as a result of advancements in the field of science and medicine. It has proven medicinal effects in various animals as well as human clinical trials and is safe and non-toxic even at high doses [42–46]. Due to its anti-inflammatory, antioxidant and chemotherapeutic properties, it has shown promising results in patients with cancers, peptic ulcer, gastric ulcers, diabetes, ulcerative colitis, renal disorders, acquired immunodeficiency syndromes, arthritis, cardiovascular diseases, rheumatism, hepatic conditions, anorexia, sinusitis, cough and thalassemia [3, 47–50]. It has also demonstrated anti-parasitic, and antibacterial properties against Plasmodium falciparum, Leishmania major, Staphylococcus aureus, Salmonella paratyphi, Mycobacterium tuberculosis, and Trichophyton gypseum types; with some antiviral properties as well [4, 51–54].
AD is a common cause of dementia resulting in cognitive loss and behavioral changes that gradually increases with time [8, 55]. So far no effective treatment has been developed to stop, prevent or reverse the damage caused by AD [56] and that is the reason that presses the need for exploring and developing new therapeutic agents with efficacy, safety and cost effectiveness to delay the progression of diseases [57]. Some previous epidemiological studies have suggested that non-steroidal anti-inflammatory drugs play their role in the reduction of brain inflammation which is a characteristic of AD [53].
Natural products derived from medicinal plants and herbs can be a rich source of non-steroidal anti-inflammatory drugs. It is assumed that the lower prevalence of AD in south Asian countries might be due to the regular usage of turmeric as part of curry [57]. In 2006 population-based study was conducted to find out the effectiveness of curry on cognitive abilities of elderly individuals [58]. Their survey concluded that individuals who regularly use turmeric as part of their curry have better cognitive abilities and suggested that turmeric might be explored through more detailed systematic studies for this quality [59]. Due to stronger antioxidant properties and lack of side effects associated with many anti-inflammatory drugs, considerable research has been carried out on curcumin in various types of animal models [31, 43].
Extensive research has been carried out on the effect of curcumin on Alzheimer’s disease in the last decade most of which suggest the presence of anti-amyloid properties in curcumin. In vitro studies revealed that curcumin inhibits Amyloid AB aggregation and oligomerization [60–63]. It has the ability to stimulate disaggregation of existing amyloid deposits, reducing the size of existing deposits and preventing aggregation of new amyloid deposits [64–66]. Curcumin has also been found to have modulating effect on proteins phosphorylation, thus avoiding the formation of neurofibral tangles [66, 67]. Besides, curcumin is also used for imaging β amyoid plaques and various curcumin based fluorescent β amyloid imagining compounds have been made and assessed both in-vivo and in-vitro, suggesting that curcumin-based dyes can be a better alternative with no side effects [68, 69].
Curcumin in sleep disorders
Sleep disorders are naturally linked with increased psychotic problems such as anxiety, depression and fatigue resulting in lower quality of life. Some of the common sleep disorders observed by individuals belonging to various age groups are insomnia, restless leg syndrome, sleep paralysis, sleep walking, nightmare disorder and bruxism [70]. Along with these, the most common and significant change correlated with aging is the serious disruption in the sleep wake cycle of an individual. More than 50 percent old aged individuals complain about the difficulties related to initiating and maintaining sleep [71]. These sleep disorders are directly or indirectly caused due to abnormality or inability of the brain cells to function properly. Poor sleep is one of the major risk factors of increased morbidity and mortality [70].
Extensive research work has been carried out on curcumin proving its neuro-protective, anti-apoptotic, and pro-regenerative effects on the cells of central nervous system even when administered at lower doses [57]. It has the ability to regulate the neurotransmitter levels in brain and rising the neurotropic factors boosting neuronal survival [72]. Therefore, suggesting that curcumin can be a safe and effective therapeutic agent for preventing the progression of symptoms such as sleep deprivation, social withdrawal and susceptibility to stress [63, 73].
Conclusions and future directions
Sleep is a fundamental process associated with physiological maintenance of various systems and neural restoration. Proper well balanced and healthy sleep plays an important role in the enhancement of cognitive abilities such as memory consolidation and the clearance of metabolic waste materials from CNS. Conversely, sleep deprivation or sleep loss is associated with multiple side effects such dysregulation of circadian processes, loss of cognitive abilities and emotional instability. Sleep disorders are very prevalent, severe and usually not assessed and treated in patients, as usually they are being associated with some other issues.
Along with other neurodegenerative diseases, AD greatly affects the cognitive abilities of an individual and is increasing in our communities very rapidly. Based on sleep analysis and its disorders, it is strongly needed to identify new therapies for AD mostly effective at the pre-symptomatic stages. In the last few decades, extensive research has been carried out on curcumin proving its non-toxicity and effectiveness against a wide range of diseases. One of the best pro side of using a plant based product as medicine is its non-toxic effects on other systems of the body, and that is why curcumin a good prospective candidate for future as medicine against many neurodegenerative disorders, besides it effectiveness against Alzheimer’s syndrome. Curcumin can improve cognitive functions as proved by various experimentations of animal models. It can be used to develop a non-steroidal anti-inflammatory drug for the treatment of AD that can restore the lost functions of brain cells. In future, such techniques are needed to be developed that should be able to diagnose AD at the pre-symptomatic stage in individuals that have a family history of Alzheimer’s.
Limitations of the study
A search for unpublished literature or dissertations was not performed. Studies in languages other than English were excluded, which resulted in a low number of full texts available for this review.