User:BroSamV/Alkaloids in Alzheimers Disease

Alkaloids

Alkaloids are a class of nitrogenous compounds that are used and produced by plants. Alkaloids have various critical physiological effects on humans. Particular alkaloids have been known to assist in the treatment and prevention of Alzheimer’s disease. This is an irreversible neurodegenerative disease that affects various expressions of the brain such as cognitive, memory, and behavioral impairments. Various alkaloids such as berberine, caffeine, morphine, and galantamine have played an imperative role as therapeutic drugs on a molecular level to prevent or at least significantly slow down the effects of Alzheimer's disease.

Berberine

This is the organic structural form of the alkaloid known as berberine. It is derived from herbaceous plants and offers a neuroprotective role to assist the neuronal development by inhibiting the accumulation of acetylcholinesterase. It also helps manage and regulate the levels of oxidative stress.

Berberine is an alkaloid that is highly useful in the prevention of Alzheimer’s disease. It is sourced from plants that restrict the plaques made by amyloids and intracellular neurofibrillary tangles. Berberine offers a neuroprotective role to sustain the prolonged development of neurons and facilities how oxidative stress is regulated. This alkaloid comprises a lipid glucose ability in which it will lower those amounts which can be used as a protective agent in dementia. This alkaloid selectively targets AChE (acetylcholinesterase) and inhibits it from accumulating. This is critical since the degradation of this enzyme can lead to potential cognitive dysfunction and raised levels of dementia When the production of AChE is halted, cholinergic nuclei will be restored since acetylcholine levels will not be declined. Berberine also manages and facilitates the levels of oxidative stress. It does this by regulating the B and Y-secretase which forms the production of neuroinflammatory processes. Berberine regulates these factors by increasing the progression of oxidant-antioxidant balance and reducing the harmful stress caused by B and Y-secretase. Oxidative stress occurs from the outcome of uncontrolled reactive oxygen species (ROS). ROS has been known to be a very imperative factor in neuronal dysfunction and cell death which allows for the disease of Alzheimer’s to become more virulent. Berberine can also promote ROS-preventing mechanisms by causing peroxynitrite scavenging activities which include strong oxidizing properties to help ultimately prevent Alzheimer’s disease. Berberine helps prevent dementia by cleaning out impaired cells through one of its benefits of inducible autophagy. It will help regenerate much healthier cells by decreasing APP and BACE1 levels which are two enzymes that increase oxidative stress and AChE levels.

Caffeine

This is the organic structural form of the alkaloid known as caffeine. Varying PKA levels in mice caused by this caffeine is very critical in determining if a specific gene is activated and can trigger enhanced or decreased plaque formation which is imperative in the progression of Alzheimer’s disease.

Caffeine can help slow down the progression and reduce the symptoms of Alzheimer’s disease. Caffeine allows for positive effects by decreasing PKA levels and regulating oxidative stress. A study conducted on mice treated with 1.5mg/d for half a year resulted in normalized PKA levels but without the implementation of caffeine, decreased PKA levels. This is important in preventing Alzheimer's disease because when PKA levels are reduced, a gene known as the c-Raf-1 gene is activated which leads to high levels of plaque formation. However, with the addition of caffeine, PKA levels were standardized and prevented the activation of the c-Raf-1 gene, leading to much lower levels of plaque formation. Caffeine serves as a very effective antioxidant compound. The correct dosages of this alkaloid can reduce high levels of oxidative stress and by apoptosis, increasing antioxidant capacity. Without this process, there can be an increased chance of developing Alzheimer’s disease. An allele known as the apolipoprotein E (ApoE) allele can be a huge factor in determining the rise of the disease. If an individual possesses the ApoE allele in their genetic makeup, they can have increased cholesterol levels from an aggressive type of cholesterol transport from the blood into the brain. The cholesterol is transported from astrocytes to neurons. The increasing levels of cholesterol found within the individual with the ApoE allele can dramatically increase oxidative stress leading to Alzheimer’s disease. Fixed caffeine dosages can reduce reactive oxygen species and can drastically reduce this risk. Additionally, a study found that mitochondrial function can be greatly improved in neurotoxic conditions by chronically intaking caffeine which also manages high levels of oxidative stress. This will also prevent the derangement of red blood cells.

Morphine

This is the organic structural form of the alkaloid known as morphine. It is a very strong opioid that has been tested on rats and proven to protect cells against neuroinflammation and amyloid-beta uptake. It has been noted that regular prescribed dosages of this drug actually worsen the effects since mice with dementia already release natural endorphins. Smaller dosages do provide better relief.

Alzheimer’s disease is caused by heavy damage to neuronal cells in the brain. Studies tested on rat brains in vivo and mainly neuronal cultures demonstrate that morphine protects neurons against microglia-mediated neuroinflammation and amyloid-beta uptake. It also protects against intracellular amyloid toxicity by inducing estradiol release and the upregulation of heat shock protein-70. Morphine also plays a critical role acting as a protective mechanism by regulating beta-amyloid metabolism. Alzheimer’s disease can exponentially progress by beta-amyloid peptides increasing in the brain. Morphine reverses the electrophysiological changes done to beta-amyloids and aids to reduce the intracellular amyloid-beta accumulation. One of the early critical events of Alzheimer’s disease is the buildup of intracellular amyloid-beta peptides. This can also potentially lead to the neuronal damage of cells. Morphine, along with endorphin-1 and endorphin-2 protects against intracellular amyloid-beta peptide toxicity. Morphine will trigger a substantial amount of estrogen released from hippocampal neurons, which will result in the upregulation of the heat shock protein 70 (Hsp70). As described earlier, Hsp70 aids in the protection against intracellular toxicity by elevating the levels of proteasomal activity, which initially is diminished by intracellular amyloid-beta peptides. A study was conducted in rat hippocampal cultures of neural cells where morphine was added, along with endorphin-1 and endorphin-2, which demonstrated reduced cell death triggered by intracellular amyloid-beta peptides by ~25 percent. They compared results of microinjecting regular amyloid-beta peptides in the rats and injections of morphine (with endomorphin-1 and endomorphin -2) in rats. Injection with normal amyloid-beta peptides induced ~40 percent cell death 24 hours post-injection, but morphine (along with endomorphin-1 and endomorphin-2) protected cell death by ~50 percent. It is important to note that other studies have also demonstrated that opioid-based painkillers such as morphine are also causing more harmful side effects than actual relief to individuals with dementia. A study on mouse models was conducted to compare why patients with dementia were actually getting worse when given opioids such as morphine. The results concluded that mice with Alzheimer’s disease were substantially more prone to sensitivity to the effects of morphine and needed much less for pain relief. Scientists discovered that mice with dementia initially release much greater levels of the body’s natural opioids (endorphins). Patients do get relief from opioids, but in much smaller dosages than prescribed and are especially much more sensitive to adverse effects when dosages are higher.

Galantamine

This is the organic structural form of the alkaloid known as galantamine. It uses its hydroxyl group to effectively bind to acetylcholinesterase to lower the amount of acetylcholinesterase that is produced, which ultimately will allow the neurotransmitter, acetylcholine to increase allowing for a diminished decline in cognitive ability.

Galantamine is an alkaloid derived from the isoquinoline alkaloid family. It was initially used as an alkaloid to treat poliomyelitis. Alzheimer's disease is highly reliant on the effects caused by glutamatergic and cholinergic systems. Galantamine functions as an inhibitory alkaloid that prevents acetylcholinesterase and regulates nACHR activity. Acetylcholinesterase levels are decreased in the synaptic cleft once galantamine is bound to it in the brain but also modulates nicotinic neurotransmission. This is imperative because regulation of these receptors will increase dopamine and glutamate which are critical in the prevention of dementia and enhancement of the normal brain processes. Galantamine consists of a hydroxyl group on the alkaloid that assists in the effective binding to acetylcholinesterase. This is critical because this binding assists in significantly decreasing AChE activity allowing for much less cognitive decline straying away from leading up to Alzheimer’s disease. Acetylcholine is involved in learning, normal brain function, and other memory developments. When nerve cells face disruption or begin to die out, acetylcholine is affected since it begins to perish away along with nerve cells. When cells are healthy, acetylcholinesterase will assist in the collapse of Ach to prevent excessive clogging up. Galantamine will reverse this process and block acetylcholinesterase, therefore allowing Ach to increase once again. This is why this alkaloid is now not only isolated, but synthesized to be more specific, and acts as a reversible acetylcholinesterase inhibitor. This will help treat the symptoms but still don’t provide an optimal solution to make the disease less pathogenic.