Pharmacogenetic Considerations in the Treatment of Alzheimer’s Disease

Cacabelos, Ramón; Torrellas, Clara; Teijido, Óscar; Carril, Juan Carlos

doi:10.2217/pgs-2016-0031

Cited by 44 publications

(39 citation statements)

References 163 publications

(251 reference statements)

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“…Genes involved in the pharmacogenetic network include pathogenic, mechanistic, metabolic, transporter and pleiotropic genes [9,10,11,12,13,14] (Table 1), and all these genes are also under the influence of epigenetic modifications (DNA methylation, histone/chromatin remodeling, mRNA regulation) [12,13,14]. In recent years novel evidence has demonstrated the impact of pharmacogenetics on antiparkinsonian drug efficacy and safety [9,17,90,91,92,93] (Table 1).…”

Section: Pharmacogenomicsmentioning

confidence: 99%

“…Although the primary cause of neurodegenerative disorders and the pathogenic mechanisms underlying protein conformational changes and premature neurodegeneration are unknown, recent advances in genomic medicine (structural and functional genomics, epigenetics, transcriptomics, proteomics, metabolomics, pharmacogenomics) have greatly contributed to better understand the complex processes responsible for age-related neuronal death in neurodegenerative disorders [9,10,11,12,13,14]. …”

Section: Introductionmentioning

confidence: 99%

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Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Cacabelos

2017

IJMS

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431

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Parkinson’s disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the “wearing-off phenomenon”, with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics.

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Section: Pharmacogenomicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Cacabelos

2017

IJMS

Self Cite

431

300

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“…In a previous study we demonstrated that the effect of Atremorine on DA levels is highly influenced by polymorphic variants in genes of the pharmacogenetic network [18]. The presence of the APOE-4 allele is a major risk factor for dementia [20,21,30], and APOE-3/3 carriers are the best responders to anti-dementia drugs, whereas APOE-4/4 carriers are the worst responders to conventional treatments [20,21,30]. This study reveals that APOE-3 carriers are also better responders to Atremorine than APOE-4 carriers (▶ Fig.…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetics of Atremorine-Induced Neuroprotection and Dopamine Response in Parkinsonʼs Disease

et al. 2019

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Atremorine is a novel bioproduct with neuroprotective effects on dopaminergic neurons and a natural L-DOPA donor in Parkinsonʼs disease (PD). In the present study, we show the effects of a single dose of Atremorine (5 g, p. o.) on plasma dopamine (DA) response and brain function in PD (n = 183) and the influence that pathogenic (LRRK2), metabolic (CYP2D5, CYP2C9, CYP2C19, CYP3A5, NAT2), transporter (ABCB1), pleiotropic (APOE), and detoxifying genes (CYP1B1, GSTT1, GSTP1, GSTM1, SOD2) involved in the pharmacogenetic network exerts on Atremorine-induced DA response. Over 90% of PD patients at diagnosis show plasma DA levels below 20 pg/mL. Atremorine induces DA synthesis causing a significant increase in plasma DA levels 1 h after administration in practically 100% of patients. Females tend to show lower basal DA levels than males and the response of DA to Atremorine is stronger in males than in females. Atremorine-induced DA response is pharmacogenotype-specific and lasts from 6 – 12 h depending upon the pharmacogenetic profile of each patient. Genetic variants in pathogenic genes, metabolic genes, and genes involved in the detoxification processes affect the response of DA to Atremorine in a genotype-specific manner. Atremorine or any of its bioactive components can cross the blood-brain barrier and improve brain function and motor function, as revealed by the reduction in slow wave activity in brain mapping and psychometric assessment, respectively. Atremorine is a selective neuroprotective agent for dopaminergic neurons with prophylactic and therapeutic potential in PD.

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“…Genomics uses advanced sequencing technology and informatics to unravel the human genomic profile in health and disease. Genomic studies can assist in identifying multiple genes pointing to specific pathways in which interventions might be able to impact a network of interacting pathophysiologies [15]. Dr. Martin Schiller, a key UNLV collaborator of the CNTN, discusses genomics as an important means for advancing understanding and treatment of NDD.…”

mentioning

confidence: 99%