Introduction
Chronic inflammation in the central nervous system (CNS) is a hallmark of neurodegenerative disorders such as Alzheimer’s disease. The etiology of neurodegeneration is diverse, and evidence indicates that extrinsic variables such as lifestyle and chemical exposures are connected to the development of these disorders. Neurotoxic metals have been linked to AD due to their potential to increase beta-amyloid (Aβ) peptide levels and phosphorylation of tau protein (P-tau), resulting in senile/amyloid plaques and neurofibrillary tangles (NFTs), both of which are symptoms of the disease. The prevailing neurodegenerative condition majorly analyzed is dementia with the maximum cases being Alzheimer’s disease type. The paramount risk factors of AD are, age greater than 60 years, low schooling, family background, and rural residence. Alzheimer’s disease is responsible for two-thirds of all dementia cases worldwide.
Cholinergic neuron depletion has been reported in 70% of AD patients and 40% of vascular dementia (VaD) patients in neuropathological studies. Attenuated acetylcholine (ACh) levels in the cerebral cortex, hippocampus, striatum, and cerebrospinal fluid (CSF) have been reported in VaD patients. A buildup of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) is thought to be the cause of neurodegeneration in Alzheimer’s disease. Because of their toxicity, Aβ plaques cause synaptic dysfunction and neuronal death and increase tau phosphorylation. NFTs are generated when phosphorylated tau aggregates and play a role in neuronal dysfunction and cell death. The deposition of Aβ and NFTs disrupts glutamate transmission at synapses and the resulting increase in glutamate at the axon terminals is linked to cognitive impairment.
Because there is presently no cure for AD, both patients and their caregivers must focus on symptom management. Microglia and astrocytes are the primary glial types involved in inflammatory reactions. Astrocytes play a role in synaptic information transmission and plasticity, neurotransmitter metabolism, metabolic trophic, and antioxidant support for neurons, and brain homeostasis. Furthermore, astrocytes are immunocompetent players, generating a wide range of inflammatory mediators, including pro- and anti-inflammatory cytokines, in response to diseased or injury conditions. The goal of this study is to look at the effects of Alzheimer’s medicines on brain tissues by looking at the interactions between neurons, astrocytes, and microglial cells.
Neuron-glia interaction
Neuron-glia interactions may be dysfunctional in the pathophysiology of neurodevelopmental disorders. The identification of novel treatment targets for neurodevelopmental diseases will be aided by a better knowledge of the mechanisms governing neuron-glia interactions during synapse development and maturation. It has been indicated that several newly discovered characteristics of glial cells, like the release of gliotransmitters and cytokines, promote their interaction with neurons throughout brain development.
Glutamate and gamma-aminobutyric acid (GABA) are examples of gliotransmitters in addition to cytokines that are known to function at tripartite synapses and may either directly or indirectly affect the well-being of neurons. It would be essential to study the interconnections of both glia and neurons in the current brain science. Glia, rather than nerve cells, have become the focus of several kinds of research on dementia and aging.
Astrocytes are the mass innumerable subtypes of glial cells within the central nervous system (CNS). The cell body and the vital processes of astrocytes are enhanced with glial fibrillary acidic protein (GFAP) that forms intermediate filaments. Astrocytes are a crucial component of synaptic transmission, modulate brain energetics, and moderate cerebrovascular function, and therefore are important for the organization and maintenance of neuronal health.
Donepezil
Introduction
Donepezil hydrochloride is a well-known anti-dementia medicine that works by inhibiting acetylcholinesterase, which raises acetylcholinesterase levels. It is an acetylcholinesterase inhibitor (AChEI) that is used to maintain AD symptoms.
Pharmacokinetics
Absorption is adequate via oral administration with 100% of relative oral bioavailability in which it attains peak plasma concentration in 3-4 hours.
Mechanism of actions documented by previous experiments and clinical research
Donepezil is one of the cholinesterase inhibitors whose mechanism of action involves binding with enzymes such as acetylcholinesterase thereby blocking the hydrolysis of acetylcholine to boost cholinergic neurotransmission. The binding and deactivation of AChE by donepezil cause acetylcholine (ACh) hydrolysis to be suppressed, resulting in an increase in ACh buildup at cholinergic synapses.
Dosing
10 mg of donepezil improved cognitive function slightly more than 5 mg. A new high dose of one per day 23 mg tablet was endorsed for treating Alzheimer’s disease patients with mild to moderate symptoms. It had also been hypothesized that inhibition of cortical acetylcholinesterase (AChE) function is 20-40% using 5 mg and 10 mg thereby demonstrating that AChE inhibition is directly proportional to the dose of donepezil.
Effects on clinical presentations and documented pathologies
After six months of medication, the effects of donepezil on clinical biomarkers of AD indicated a decrease in serum content of amyloid-beta (AB) in AD patients. In addition, donepezil improved cognitive performance by slowing hippocampal atrophy and lowering total tau protein expression.
Galantamine
Introduction
Galantamine is a natural substance derived from the bulbs of various Amaryllidaceae species and the Caucasian snowdrop. It is an allosteric nicotinamide acetylcholinesterase receptor (nAChR) modulator and a selective, reversible, competitive inhibitor of acetylcholinesterase inhibitors (AChEI). Galantamine is an acetylcholinesterase inhibitor that also increases acetylcholine release, which allosterically amplifies the effect of acetylcholine at the nicotinic receptors.
Pharmacokinetics
Galantamine had been shown to increase the secretion of other neurotransmitters like glutamate, gamma amino butyric acid, and various monoamines via this allosteric mechanism.
Mechanism of actions
Galantamine has been shown to block astrocyte activation, lower intracellular tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) expression, and reduce the total amyloid load in the hippocampus of amyloid precursor protein.
Dosing
Galantamine may give neuroprotective against the amyloid-beta peptide, which is involved in the etiology of Alzheimer’s disease.
Effects on clinical presentations
70% of galantamine-treated patients improved their cognition. Electron paramagnetic resonance (EPR) imaging can be used to quickly and quantitatively assess the efficacy of disease-modifying medications for Alzheimer’s disease.
Dextromethorphan
Introduction
Dextromethorphan is a cough suppressant, although it has been around for a long time as an over-the-counter decongestant.
Pharmacokinetics
Dextromethorphan (DM) has a complicated pharmacology that goes beyond blocking N-methyl-D-aspartate receptors (NMDAR) and inhibiting glutamate excitotoxicity. Serotonin transporters, noradrenaline transporters, sigma-1 receptors, and N-methyl-D-aspartate receptors are all involved in the pharmacology of DM. DM has no meaningful activity at opioid receptors, despite its structural similarity to opioid agonists.
Mechanism of action
The use of DM may potentially generate agonist activity at sigma-1 receptors via antagonizing nicotinic acetylcholine receptors, particularly those made of 3 4 subunits.
Dosing
DM had considerable effects on glial proliferation in less mature cultures compared to minor variable effects in mature cultures. The fast metabolization of DM to dextrorphan (DX) has impeded the development of DM therapies. Due to quick and widespread conversion to DX, when DM is given orally (30 mg) to extensive metabolizers, only modest plasma levels are attained.
Effects on clinical presentations and documented pathologies
DM reduced lesion size and neuronal cell death, potentially via lowering microglial activation. NMDAR-mediated excitotoxic brain damage induced by inflammation was reduced by low dosages of DM without affecting neuronal death.
Palmitoylethanolamide
Introduction
Palmitoylethanolamide (PEA), a natural compound from peanut meal, egg yolk, and soybean lecithin, is an analog of anandamide. PEA, like other endogenous N-acylethanolamine compounds, is known to mimic several endocannabinoid-driven actions even though it does not bind to cannabinoid receptors.
Pharmacokinetics
Glial cells produce palmitoylethanolamide, a lipid messenger that arises naturally as an amide of ethanolamide and palmitic acid. PEA is thought to affect local cells, degradation, and the creation of various inflammatory mediators such as neurotrophic factors and TNF-alpha
Mechanisms of action
PEA therapy generates a considerable reduction in astrocyte activation with matching neuronal protection in both mixed neuroglial and organotypic hippocampus cells.
Dosing
PEA as an endogenous lipid mediator has been regarded to be a favorable pharmacological representative as it has disclosed potency in dwindling neuroinflammation and neurodegeneration in various in-vitro and in-vivo prototypes.
Effects on clinical presentation and documented pathologies
PEA has been demonstrated to be neuroprotective in models of Parkinson’s disease, spinal cord injury, traumatic brain injury, and stroke and has been implicated in the preservation of cellular homeostasis in cases of inflammation.
Promising pharmacological targets and interventions in Alzheimer’s disease
Because glia-neuron interactions are exceedingly complicated, new approaches and strategic targets should be required for the development of effective preventive and therapeutic drugs for AD and other neurological illnesses, rather than individual glia or neurons as in the past. Inhibition of the β-secretase and γ-secretase (GS) enzymes, which are known to catalyze Aβ plaque development and the consequent AD, could prevent Aβ plaque production and the resulting AD.
The occurrence of oxidative damage in neuronal lipids and proteins, in particular, is a key characteristic of AD, firmly linking oxidative stress to the disease. Because signs of oxidation exist in mild cognitive impairment brain areas, oxidative stress may be an early event in the etiology of AD which can come from a variety of places, but an excess of ROS is thought to be a primary contributor.
Medication that addresses the control of glia-neuron connections may offer a novel therapeutic strategy for AD in its early stages. When the glia fails to respond to their normal regulatory feedback mechanism, a good medicine for the treatment of Alzheimer’s disease would be effective by targeting the lowering of glial activation and recruitment. Neurodegenerative disorders may respond very well to such medications that can lessen neurotoxicity in the nearby brain brought on by activation of microglia produced by an excess production of pro-inflammatory cytokines like interleukin (IL)-1 and TNF.
Additionally, glia-neuron interactions, glutamate absorption, and neuronal connections and synapses may be maintained by drug repurposing that focuses on reducing the negative effects of reactive astrocytes. Cyclin-dependent kinase-5 (CDK5) plays an important neuro-differentiation and neuroprotective role in healthy neuronal functioning and has been associated with several neurological disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.
Conclusion
This review investigated how astrocytes and microglia preserve neurons in normal conditions, how connection among neurons, astrocytes, and microglia try to control inflammatory feedback and traumatic stress handling, and how these glia cells end up losing their neuroprotective effect for neurons while becoming toxic in Alzheimer’s disease. The drugs were evaluated as per their pharmacokinetic features, underlying mechanisms, dose as established by previous experimental and clinical research, clinical effects, and documented pathologies. Existing medications are aimed at keeping Alzheimer’s disease symptoms at bay. As a result, the quest for medications that can reduce the degenerative process in dementia patients is still critical. Donepezil is capable of reducing amyloid-beta (Aβ) levels in the blood, reducing total tau protein expression, and improving cognitive function by decreasing hippocampus atrophy after 48 weeks of treatment. Donepezil and galantamine did not affect astrocyte proliferation.