Figure 1: Structure of Atropine. Atropine is the classic "Tropine alkaloid" a plant substance containing N-CH3 structure mimicking the business end of Acetylcholine.

Witch’s brews are derived from plants whose common names may be familiar containing powerful Tropane Alkaloids. These include henbane (Hyoscyamus niger), pituri (Duboisia spp.), and mandrake (Mandragora officinarum).

“Jimsonweed” from Jamestown weed. In 1676 British soldiers stationed in Jamestown, Virginia became intoxicated by D. stramonium when it was inadvertently included in their salads by the regimental cooks. The episode was widely publicized and the plant culprit became known as "Jamestown weed", and later as jimsonweed.

The Datura contain powerful plant alkaloids belong the nightshade family along with the tomato, eggplant and the potato, close relatives but economically extremely important.

Figure 2:Drs. Selcoe (l) and Weiner

Figure 3: Stanley Prusiner

Figure 4: Scematic of a senile plaque

Figure 5: Microscopic picture of a senile plaque

Figure 6: Secretases and Amyloid Precursor protein both straddle the cell membrane

Figure 7: Neurofibrillar tangle. note bundles of fibrils composed of Paired Helical Filabments

Alzheimer Genes: Chromosome #s

•21: Abn APP Gene <5%*

•14: Presenilin 1 18-50%*

•1 : Presenilin 2 <1%*

•19:APOE-epsilon 4: Incr risk in Caucasions

•19:APOE-epsilon2 on Chr 19: decr risk

*of early-onset Disease

Neurologic Diseases attributed to Protein deposition

•Alzheimer disease: Aβ42

•Amyloid Angiopathy: Aβ42

•Huntington Disease: Huntingtin

•Prion Disease: PrP sc

•“Tauopathies”: Pick’s, FT dementia, PSP

•Parkinson Disease, Lewy body Dementia (alpha synuclein)

•Spino-cerebellar Degenerations: Ataxins

•ALS: Neurofilament

•Macular Degeneration: A2E

[1] “Jimsonweed” from Jamestown weed. In 1676 British soldiers stationed in Jamestown, Virginia became intoxicated by D. stramonium when it was inadvertently included in their salads by the regimental cooks. The episode was widely publicized and the plant culprit became known as "Jamestown weed", and later as jimsonweed.

[1] In addition to having profound effects in the brain ACh is the transmitter at the neuromuscular junction, secreted by nerve endings that makes muscles contract. When you want to bend your elbow, acetylcholine is secreted by the nerve endings at the biceps muscle signaling the biceps to contract. Aceylcholine also is the transmitter in the sympathetic and parasympathetic nervous system ganglia. The sympathetic nervous system is used for “fight or flight” that excitation allowing an animal to suddenly activate to avoid a predator or danger or conversely to attack including startle, stimulating the heart to contract, mobilizing energetic compounds such as fats and sugars, shutting down systems that aren’t immediately necessary for survival in a fight to the death, such as the gastro-intestinal tract. These functions describe one particular effect of ACh called the nicotinic effect. Yes, that is the same nicotine as in cigarettes. It is an extremely powerful part of ACh action but, as it turns out, not particularly important as regards side effects of the four cholinesterase inhibiting drugs described above.

Another more clinically important family of ACh effects are termed muscarinic. There is where more side effects emerge. Muscarinic effects are many. They are the end organ effects of the parasympathetic nerves, often perform the opposite function of the sympathetic nerves. Parasympathetic nerves have muscarinic effects that include stimulation of the gastrointestinal tract. Smooth muscle in the gut contracts more vigorously and you can have nausea and diarrhea. Because the gut is moving so much there may well be a sort of mild dyspepsia and nausea that includes increased stomach acid secretion and an unwillingness to eat manifest as decreased appetite. Some of this gets very tricky because Alzheimer’s patients tend to be inarticulate, have trouble expressing themselves, won’t say much but perhaps may stop eating and lose weight. This does happen occasionally when we use these drugs. Others find it unpleasant, may have loose stool or even diarrhea, crampy abdominal pain and the like. There is sometimes increased salivation as well. Other muscarinic effects include miosis (pupil constriction), which doesn’t generate complaints, slowing of the heart rate (the opposite of the sympathetic nervous system that increases heart contraction) that also proves to be clinically unimportant, and enhancing bladder contraction. Your bladder is a muscular bag holding urine. Stimulating contraction of the bladder may increase urinary urgency and frequency. Lots of elderly men are taking medicines to decrease urinary urgency induced by their having enlarged prostates, a problem that causes them to awaken at night to void. Some of these drugs are anti-muscarinic, in other words have the opposite effect of the Aricept, Exelon, and Reminyl. In fact, doctors are often juggling the effects of medicines that have diametrically opposite effects because of different problems in the urinary and central nervous systems, especially in older patients which makes things difficult.

Certain insecticides and organophosphate nerve gases such as Sarin bind irreversibly to AChE the enzyme that breaks down ACh and guess what, provide an extreme view of adverse effects of mild reversible AChE binders such as our Alzheimer drugs. Click here for a little fuller discussion of their effects[1].

In the brain there are nicotinic receptors but the bulk of action is muscarinic. There are two kinds of muscarinic receptors designated M1 and M2. M1 receptors are most common in the cortex of the brain and this is the most important place where the esterase drugs work. M2 receptors are in the basal forebrain areas which release ACh and governs how much transmitter is released. M2 receptors too are highly reduced in Alzheimer patients. There are also regulatory Nicotinic receptors are also presynaptic which may be clinically important in promoting the release of ACh. Reminyl seems to affect brain nicotinic receptors.

[1] Alzheimer’s does shorten life. One study Wolfson et al NEJM 2001;344:1111-1116 found that taking some statistical rules into consideration the average life expectancy after the diagnosis of Alzheimer’s disease may be as short as 3.3 years, comparable to some bad malignancies. Other estimates are a good deal longer.