Newsfeed display by CaRP ALZHEIMER¡¦S DISEASE & ALTERNATIVE THERAPIES

Alzheimer¡¦s Disease (AD) is the leading cause of senile dementia in the US today. The impact of this disease is not confined to the sub-population of those more likely to develop AD but extends to those who must interact with the elderly, namely caretakers and other family members. The effects of the increasing number of AD patients also affects everyone in our society via the rising costs spent on AD patient care.

This disease is a neurodegenerative disorder that is characterized by progressive loss of cognitive functioning, which often results in complete dementia. Patients usually begin with short term memory deficits, constructional apraxia (impairment of basic visual/motor integrative ability) and loss of spontaneity which later continues into dysphasia (impairment of speaking / writing abilities), agnosia (inability to comprehend familiar objects), and general disorientation and behavioral disturbances. AD patients¡¦ brains show atrophy in the cortical gyri due to cell death and loss of neuronal fibers and synapses. (Feldman, et al. 1997)

Conventional therapies include cholinesterase inhibitors that address one of the AD issues, inadequate acetylcholine (ACh) and degradation of these pathways. There is no cure for Alzheimer¡¦s Disease while a high demand for some control over the disease exists. Additionally AD caregivers are often unsatisfied with the conventional therapies because of moderate efficacy and potential side effects. Thus, we see a trend in research to find new cholinesterases and to determine efficacy of alternative therapies such as antioxidant, herbal remedies and combination therapies.

In order to understand the various methods of therapies it is important to understand some of the basic neurochemical characteristics and mechanisms behind AD. AD involves significant damage to some important cortical nuclei as well as deterioration and decrease in number of synaptic connections in the cortex and hippocampus. Acetylcholine neurotransmitter systems seem to be compromised in AD patients. In the cortex, hippocampus, and amygdala there are significant losses of cholinergic neurons and cholinergic markers (i.e. ChAT, AchE). The densities of specific cholinergic receptor subtypes, muscarinic M2 and nicotinic receptors are reduced while other cholinergic receptors are not. This may be due to the possibility that M2 and nicotinic receptors are located presynaptically where they function in modulating the release of other transmitters postsynaptically. Since there is usually damage to cholinergic afferents and retention of postsynaptic cells, it makes sense that there would be this type of differential loss of these receptor subtypes. There is also speculation that other neurotransmitter systems may be compromised in AD. These include the noradrenergic and serotonergic systems, both of which are probably compromised due to the presence of neurofibrillary tangles in the nuclei mainly responsible for the synthesis of these neurotransmitters.

Physiologically speaking, the classical sign of AD are the neurofibrillary tangles (NFT) and AƒÒ amyloid plaques, which develop in areas of the neocortex, hippocampus, amygdala and nuclei of thalamus and hypothalamus. AƒÒ amyloid plaques are aggregations of AƒÒ peptides which have gone through abnormal protein biogenesis. Gene expression for the Amyloid precursor protein is subject to stresses and exogenous factors. At critical points through the process, the amyloid protein is subjected to enzymatic proteolytic cleavages by enzymes called secretases to yield AƒÒ peptides. Errors in this process can yield abnormal Ab peptides, which can then aggregate into amyloid plaques. (Masters, Beyreuther, 1998)

Unfortunately, as yet there is no cure for AD. Subsequently, current focus of treatment is on palliative or symptomatic relief for AD patients. These treatments attempt to improve memory and cognitive functions to allow patients to function more normally in daily tasks. For example, earlier attempts for therapy used drugs that are called nootropics, also called cognitive enhancers. This structurally diverse group of drugs attempted to enhance processes of attention, memory, and learning. Piracetam is the prototype nootropic used (Figure 5). However, clinical trials of this drug showed minimal improvement in a minority of the subjects treated. Most current pharmacological treatments of AD, like nootropics therapy, are based on the cholinergic model of cognitive dysfunction in AD. Many acetylcholinesterase inhibitors (AChEIs) are prescribed to prolong the action of acetylcholine at synapses. In the early eighties, physostigmine was found to produce mild improvements in AD patients but the effects were short-lived. In 1993, tetrahydroaminoacridine, THA or tacrine was approved for use with AD treatment. Subsequent studies of the therapeutic efficacy of tacrine revealed that it has limited clinical value. Also, tacrine produces problematic cholinergic side effects such as nausea, vomiting, salivation, sweating, and lacrimation. Tacrine is even hepatotoxic for some patients. This has led to further studies of alternative therapies for AD.

The search for improved therapies to tacrine began with pharmaceutical research for new AChE inhibitors. One of these searches led to the discovery of the alkaloid compound huperzine A (HupA) found in the Chinese herbal medicine Qian Ceng Ta. This traditional remedy is prepared from the moss Huperzia serrata and has been used in past centuries in China for treating fever and inflammation. More recently, the purified compound has been used as a prescription drug in China for treating dementia. (Skolnik. 1997) Laboratory studies show that HupA is actually a more potent inhibitor of AchE than current medications like tacrine. HupA appears to bind more tightly and specifically to the deep chasm known as the active-site gorge of AChE which guides ACh molecules to the enzyme¡¦s cleaving machinery. In structural analysis of AChE complexed with HupA, researchers found surprisingly that HupA bears no resemblance to ACh and that the HupA/AChE complex binds with so few direct contacts (Figure 1a from Raves et al article). Only one strong hydrogen bond is seen as well as a large number of hydrophobic interactions within the crystalline complex. (Raves, et al. 1997). Comparison between the discussed AChEIs tacrine, HupA and physostigmine are shown (Figures 1-4). All three show the characteristic amino rings and have stable alternating pi bonding. A closer comparison between HupA and tacrine show that they are quite similar because both have primary amine groups as substituents. HupA looks like it could be three connected ring structures if the methyl group and one double bond connected. Then it would be somewhat similar in structure to tacrine. Apparently, though, it is these differences that makes it have higher affinity for the correct binding site on the AChE molecule.

In addition, compared to tacrine, HupA has a longer half-life and lacks cholinergic and hepatotoxic side effects. Studies using cells from the hippocampus and cerebellum of rat embryos have shown that HupA decreases neuronal cell death caused by toxic levels of glutamate. Glutamate activates certain NMDA receptors, which increase the influx of calcium ions followed by activation of proteolytic enzymes and subsequent cell death. These HupA advantages had led to the current clinical trials of efficacy on AD in the US.

Other studies of potential ACh therapies from compounds in herbal medicines also found some interesting results. Trasina (TS), an ayurvedic herbal medicine, is a traditional Indian medicinal plant used to improve memory and intellect. The constituents of Trasina are Withania somnifer, Ocimum sanctum, Eclipta alba, Tinospora cordifolia, Picrorrhiza kurroa, and shilajit. All are plant-derived constituents except shilajit, which is a blackish-brown exudate obtained from steep rocks of different formations found in the Himalayas. Studies were done to determine the efficacy of TS in alleviating the neurodegeneration of ACh pathways. Colchicine was administered to rats to induce cognitive defects. Though TS had minimal effects on cognitive function and cholinergic markers in absence of memory dysfunction, TS was able to attenuate cognitive deficits induced by administered colchicine. This was achieved through what is believed to be the drug¡¦s action of increasing cortical muscarinic ACh receptor capacity. There is some evidence about the actions of individual constituents of Trasina. Shilajit is shown to improve learning acquisition and engram in rats. This effects is significantly more in aged rats. W. Somnifera was found in studies of rats to improve the acquisition and retention of learning. Trasina is still in clinical trials in the US to test for efficacy and side effects in treating AD. (Bhattacharya and Kumar. 1997)

Studies, which do not focus on the cholinergic model of cognitive dysfunction in AD, are also underway. There is increasing evidence from studies to support the hypothesis that oxidative stress may be associated with onset and progression of AD. This has led to attention on antioxidant therapies, which are believed to enhance mental functions and delay cognitive losses with aging. Free radicals, any atom or molecule that contains an unpaired electron, are produced under normal conditions. However, excessive production of free radicals can lead to diseased states because these molecules often interfere with normal bodily functions. AD brains have been shown to exhibit more oxidative reactions than normal. An antioxidant is any substance that is able to protect against the damages of oxidative stress caused by free radicals. Some antioxidants are Vitamin E (high doses), selegine, ginkgo biloba (Egb). Clinical trials of antioxidants in AD are evaluating the efficacy of high dose of vitamin E and selegine in slowing the progression of AD. Preliminary results are promising and indicates need for additional clinical trials and studies. Vitamin E and selegine both do not, however, enhance cognition to the same degree as current available cholinesterase inhibitors. (Pitchumoni and Doraiswamy. 1998).

Ginkgo biloba is an extract from the leaves of the Ginkgo or maidenhair tree, Bai Guo (Chinese). Ginkgo seeds are commonly used in Chinese herbal medicine to relieve wheezing and lessen phlegm. Ginkgo leaves are traditionally used for treating asthma. In Western herbal medicine, ginkgo is used for improvement of circulation especially to the brain and is also used for its antiallergenic and anti-inflammatory actions. The leaves are Ginkgo biloba, as mentioned above, may have some antioxidant involved mechanism in treating AD. The compounds in ginkgo biloba act as scavengers for free radicals. The Egb extract contains several compounds that are thought to act synergistically on preventing oxidative stress and protecting neurotransmission modulation and membrane of neurons. Further studies are needed to fully elucidate the mechanism of EGb. It has undergone several European studies, which report positive results of EGb in the treatment of neurological disorders, and has already been approved in Germany for treatment of dementia. In studies done on AD subjects there was a modest benefit of ginkgo biloba when compared to placebo on cognition. This study compared effects of EGb to placebo in a sample of mild to moderately severe cognitive impairment. It demonstrated through objective tests of cognitive performance that EGb induced noticeable differences in patients¡¦ cognition to caregivers. (LeBars, et al. 1997).

Antioxidants like vitamin E and ginkgo biloba are beneficial because of their simplicity in treatment, ease of access, tolerability and low costs. If further studies indicate that they are complementary to the cholinesterase medications or beneficial alone in prevention of AD onset, some of the heavy burden on caretakers and elderly AD patients themselves would be alleviated. It would also prove beneficial for people who prefer ¡§natural or holistic¡¨ medications over synthetic ones.

While improved pharmacological therapies are still in clinical trials, AD patients and caregivers often use other unproven therapies such as vitamins, home remedies, ¡§smart pills¡¨, and herbal medicines. In a survey study conducted to describe the current use of unproven therapies by AD patients, roughly one-third of the caregivers reported ¡§a little¡¨ improvement with a given therapy. Caregivers who perceived a low level of physician support were not more likely to seek alternative therapies than those who perceived high physician support. This might indicate that the self-reports might not be biased due to bitter feelings toward the medical community. The reports also showed that most of those using these treatments preferred them to conventional medications because they believe that they are more natural and holistic remedies. While conventional treatments have a palliative focus, some of these unproven therapies are believed to retard progression of dementia by improving cognitive functions. Though these therapies seem like a good idea, there are potential negative effects. Since the patients¡¦ physicians do not prescribe these remedies, there maybe be adverse drug reactions with the prescribed medications. The costs of these therapies are often high and can take away from the money supply for other proven beneficial goods or services. We must also consider the ethical issues of companies selling or marketing these unproven therapies to both people with impaired cognition and caretakers who are desperate. (Coleman, et al. 1995). This is just one of the indications that improved medications and therapies must be developed soon for the growing number of AD patients.

Instead of the current monotherapy with AChEIs, perhaps combination therapies should be initiated, given the positive results in studies. Given the multiple pathological and neurochemical deficits in AD, combination therapy seems logical. (Doraiswamy and Steffens.1998). Since the efficacy of cholinesterase inhibitors has been consistently demonstrated for stabilizing or delaying cognitive losses, these medications could be the standard for any combination therapy. Alternative therapies could be used in conjunction to the cholinesterase inhibitors. Conventional AChE inhibitors could be used with a number of different alternative therapies like antioxidants, anti-inflammatory agents, estrogen, selegine, vasoactive agents, ginkgo biloba, and propentofylline (a neuroprotective and glial cell modulator). Some recommendations from a American Psychiatric Association conference in 1997 included a quadruple drug regimen of AChEI, vitamin E, estrogen, and indomethacin. Estrogen and seligiline may enhance the efficacy of AChEIs. Ginkgo biloba and propentofylline could also be used as alternatives. However, there is lack of clinical trial data for these combination therapies.

Also we should explore the possibilities of using therapies that are aimed at decreasing the amount of Ab plaques that develop. Some strategies include:

„h inhibition of Ab forming enzymes

„h inhibition of aggregation

„h promoting dissolution of Ab

„h ameliorating toxicity of Ab

„h suppressing reactive responses to Ab toxicity

These strategies would target the other neurological defect that AD patients suffer. If these are found beneficial combination therapies aimed towards the cholinergic deficits and AƒÒ plaques could further retard the damaging effects of AD.

A myriad of current and future (possible) AD treatments has been discussed. It seems that treatment possibilities would increase if researchers and herbalists internationally would come together and share their ideas and traditional remedies. Many of the possibilities mentioned in this paper have been known to cultures outside of the US for many years before the US researchers began their studies. It is a shame that the US is unable to accept the study results from other countries and must conduct studies for itself before the FDA will review these new possibilites.

Until there is more research at the molecular level and clinical trials, AD patients will have to settle for current medications and beliefs about alternative therapies. Perhaps once we can come to a better stage of medical treatment for Alzheimer¡¦s patients we might be better able to address issues of decreased emotional health many Alzheimer¡¦s patient suffer as a result of their early symptoms. Caretakers would be able to spend time with their patient in a more emotionally supportive way rather than worrying about their patients¡¦ physical and cognitive well beings.