*2.1.1 Cardioprotective actions of Ach*

ACh is found to protect the heart against a variety of pathological diseases, including isoproterenol-induced hypertrophy, hypertension, myocardial infarction, chronic chagas cardiomyopathy, and angiotensin II (Ang-II)-induced cardiac dysfunction. Cholinergic signaling was manipulated pharmacologically by using cholinesterase inhibitors such as pyridostigmine (PYR), surgically by modifying vagus nerve activity, or genetically engineered mice models to investigate the influence of variations in cholinergic activity on heart disease development. Cholinergic signaling was modulated pharmacologically with pyridostigmine (PYR), a cholinesterase inhibitor, by modifying the activity of vagus nerve with surgical procedures, or genetically engineered mouse models to examine the effect of alterations in cholinergic activity on the development of heart disease. In infarcted mice, eating improved hemodynamic measures, autonomic balance, and ventricular dysfunction. Likewise, Gavioli and colleagues discovered that PYR therapy decreased heart hypertrophy and ventricular dysfunction in two different animal models of hyperadrenergic stimulation. Even though these research findings consistently demonstrated that PYR therapies provide cardio protection in various mouse injury models, it could be fascinating to determine for certain if PYR's potential benefits have been recognized massively in human patients. In this spirit, the Alzheimer's pateints who intake the inhibitors of cholinesterase are at lower risk of mortality. The study by Li et al. described how chronic heart diseased rats survived upon the stimulation of vagus nerve. Although stimulated nerve had no effect on infarct size, it did enhance the functionality of cardiac cell and decrease hypertrophic cardiomyopathy. It is important to note here that rats whose nerve got stimulated survived 70% more compared to those that were not stimulated. Vaseghi et al. demonstrated in another work employing infarcted pigs that stimulated vagus nerve enhanced the "rest and digest" system and decreased

### *Role of Acetylcholine in Chronic Diseases DOI: http://dx.doi.org/10.5772/intechopen.110663*

abnormal heart rhythms of the ventricles, most likely by stabilizing the infarct border zones [15].

In conclusion, growing evidence suggests that cardiac cholinergic transmission (both neuronal and non-neuronal) has a biological purpose in damaged conditions, despite the fact that considerations for every ACh generator to recovery remains to be firmly defined yet.

#### **2.2 Acetylcholine and neurodegenerative diseases**

#### *2.2.1 Alzheimer's disease*

Alzheimer's disease (AD) is a neurodegenerative, inevitable, progressive disorder that affects memory, thinking behavior and other potential activities, the early symptoms of which include trouble in recalling recent talks, names or events; depression; lack of interest (apathy) and later signs are confusion, hindered communication, disorientation, behavioral changes and poor judgment [16]. Because the cholinergic system is disrupted in this condition, the "cholinergic hypothesis" was proposed. Cholinergic innervation may be disrupted even in the early stages of Alzheimer's disease, according to researchers. Neurons of nucleus basalis are especially vulnerable to this degradation. It is widely accepted about the functionality of cholinergic system that could be increased utilizing the Nicotinic/muscarinic receptor agonists and antagonists, thus these two approaches have been into action to treat Alzheimer disease. The hyperactivity of AChE produces a drop in the levels of Ach, leading to cholinergic system degeneration. The usage of acetylcholinesterase inhibitors may enhance a patient's life; however, these medications are merely indicative, meaning it results in the delaying of symptom onset, thus cannot be considered as definitive treatment. AChE activity assessments is of little relevance in the initial phases of the disease since only a small reduction in its effects has been seen. AChE is found in both the main cleft and the postjunctional fold, however the majority of it is found in the basal lamina. The location of AChE is in close proximity to the surface of a muscle as compared to the pre-synaptic layer present in the main cleft, but it is present along the whole stretch of the postjunctional fold, reaching its highest concentration down past the fold. According to research, the alterations in early AD are presynaptic. This is consistent with prior research, which found that AChE activity declines very little in early illness. Neuronal apoptosis occurs over time in Alzheimer's disease. AChE may potentially have a role in this. The tissues having more concentration of AChE are more vulnerable to apoptosis. In one of the study Tau Glycoge synthase kinase 3 (GSK3) was activated by the transfection of N-AChE-S in cell culture. GSK3 caused the tau hyperphosphorylation and apoptotic induction [17]. The amyloid hypothesis is another effort to explain the etiology of AD. Its supporters claim that the illness is caused by the buildup of protein called beta amyloid (AB) in brain. It is also thought about the neurodegeneration and symptom manifestations by these AB deposits. Amyloid beta is neurotoxic to mature neurons, causing them to die. Amyloid beta is generated by proteolysis of amyloid precursor protein (endosomal/lysosomal/at the plasma membrane surface) (APP). This process is triggered by the presence of alpha secretase (unit of preselin 1). AChE has also been found to participate in beta amyloid buildup. AChE has variable sensitivity to inhibitors in Alzheimer's disease, inhibited by indoleamine and bacitracin [18]. Furthermore, this enzyme can directly communicate with beta amyloid. The amyloid beta-AChE complex is more hazardous to the brain than only the aggregates of beta amyloid [19].

### *2.2.2 Parkinson's disease*

Parkinson's disease (PD) is a kind of neurological disorder. After Alzheimer's disease, it is the second most prevalent neurodegenerative disease. This illness is hypothesized to be caused by Lewy body (LB) and neurite aggregates. They accumulate inside "substantia nigra" (SN) & gradually degenerate the system producing dopamine neurons via neuronal destruction. The manifestations arise after half of the neurons deteriorate. Parkinson's disease also results in the malfunctioning of the cholinergic system, causing weakening of Meynert basalis nucleus, other cognitive disfigurements and hence dementia. Cholinergic deficiencies are more evident in Parkinson's disease than in Alzheimer's disease [20]. AChE activity decreases significantly with Parkinson's disease. This decline is due to the degeneration of cholinergic neurons which has decreased independently of any movement action and illness severity. Dementia patients have greater impairment in AChE activity. The individuals who were not reported with dementia but with a lower concentration of AChE in outer layer of the cerebrum have been found to have low intellectual disability, which coincides with the degradation of neurons producing choline. This association, though, varies. The number of cholinergic terminals was reduced in around one-third of the individuals. An association of various brain's areas in Parkinson's disease results in a wide range of apparent symptoms. The vulnerability of degrading choline-producing neurons of neo-cortex is more in men as compared to women [21]. An early buildup of α-synuclein in cholinergic neurons in the basal forebrain has been linked to the development of LB and neuronal loss in the SN. AChE activity was also shown to be decreased in individuals with early Parkinson's disease dementia, namely in the cerebellar medial occipital cortex. This is the location with the most cholinergic denervation. Cholinergic denervation adds to depressed symptoms in Parkinson's disease. It becomes more obvious, however, when the patient also develops dementia. βA deposits are also significant in the pathogenesis of Parkinson's disease. As previously stated, AChE may play an essential role in deposition of βA in the brain. It is probable that it will also improve Amyloid beta aggregation in Parkinson's disease. Postural instability and gait difficulties are motor subtypes in Parkinson's disease (PIGD). This kind of Parkinson's disease is distinguished by a limited sensitivity to dopaminergic medications. PIGD is one of the elements that contribute to the development of dementia. This subtype frequently has an accumulation of βA in the brain, which magnifies cognitive deficits in addition to those attributed with PIGD. It has also been demonstrated that βA deposition in Parkinson's disease patients might independently worsen apathy. In these cases, there was a strong association betweenβ A binding and apathy [22]. βA might be deposited in both the cerebral cortex and the striatum. Gait disruption in Parkinson's disease is linked to cholinergic deficiencies in the basal forebrain and an increased risk of cognitive loss. Gait speed was correlated in patients with cholinergic and dopaminergic degeneration. Furthermore, cortical AChE activity was lower than normal in certain cases. Impaired postural control and gait abnormalities are related with pedunculopontine nucleus dysfunction. Increased postural sway is related with reduced cholinergic innervation of the thalamus and, as a result, lower AChE activity. In Parkinson's disease, p-tau is also deposited. Deposition of this molecule/protein have been found in the olfactory bulb of up to 80% of Parkinson's disease patients. Its buildup is most likely linked to cognitive deterioration and the progression of dementia in patients with idiopathic Parkinson's disease. AChE increases the formation of p-tau in the brain.

### *Role of Acetylcholine in Chronic Diseases DOI: http://dx.doi.org/10.5772/intechopen.110663*

Acetylcholinesterase, furthermore, contribute significantly to the development of ocular disorders. The favorable effect has been observed on retinal development after inhibition [23]. Visual abnormalities occur in Parkinson's disease, with reasons spanning from the retina to higher cortical parts of the brain. Dopamine insufficiency is assumed to be the primary cause of the retinal alterations. Furthermore, it is not ruled out that AChE may have a role in the pathophysiology of ocular abnormalities in Parkinson's disease. Several mutations, including those in the LRRK2 and DJ-1 genes, can alter the course and onset of Parkinson's disease. In hereditary Parkinsonism, mutations in the LRRK2 gene are prevalent. It is passed down in an autosomal dominant manner. In clinical practise, this type of Parkinson's disease is not distinguishable from idiopathic Parkinson's disease. LRRK2 is involved in inflammation. The activity of AChE in carriers of this mutation was compared to that of AChE in individuals with idiopathic Parkinson's disease. AChE activity was shown to be considerably greater in LRRK2 gene mutation carriers. This is consistent with patients who carry this mutation having a shorter illness course and hence fewer severe non-motor symptoms. Enhanced AChE activity has been linked to increased neurotransmission at cholinergic synapses in the thalamus and cerebellar cortex. It is true that oxidative stress plays a crucial role in the etiology of Parkinson's disease. Its primary cause is glial cell activation. AChE receptor is the most likely type responsible for oxidative stress. Stress causes an increase in AChE by increasing the expression of this type. The rise in AChE-R is mostly due to astrocytes. In Parkinson's disease, AChE is implicated in neuronal death via apoptosis [24]. AChE expression increased in PC12 model cells for Parkinson's disease and SNpc in a mouse model. A lack of the enzyme reduced dopaminergic neuron death.
