Homocysteine and Asymmetric Dimethylarginine (ADMA) in Neurological Diseases

Homocysteine (Hcy) is formed from methionine (Met) and is distributed in two metabolic pathways: in the process of remethylation to Met and in the process of transsulfuration to cysteine. Hyperhomocysteinemia (HHcy) is a risk factor for cardiovascular and neurological diseases such as: Alzheimer’s and Parkinson’s diseases, multiple sclerosis, and stroke. Increased Hcy level may lead to endothelial dysfunction due to impaired bioavailability of endothelium-derived nitric oxide (NO). The molecular mechanism decreasing the levels of NO in HHcy conditions is incompletely understood, but it seems that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, may be a key factor. ADMA is formed from L-arginine by enzymes in the family of protein N-methyltransferases (PRMT) and may undergo hydrolysis to L-citrulline and dimethylamine with the participation of dimethylaminohydrolase (DDAH). In pathological conditions such as neurodegenerative diseases, Hcy may lead to increased ADMA concentrations by inhibiting the activity of DDAH. Several drugs, such L-dopa, antiepileptic drugs, and lipid-lowering drugs, may interfere with the metabolic pathways of thiols, leading to an alteration of plasma Hcy and ADMA levels. It seems that administration of L-arginine, in conjunction with B vitamins, to patients with HHcy may be a new method in the treatment of neurodegenerative diseases

Dopamine and Early Onset Parkinson’s Disease

Parkinson’s disease (PD) is divided into early-onset (EOPD) occurring at the age of fewer than 45 years of age and late-onset PD (LOPD) above 45 years of age. EOPD accounts for 5–10% of all the cases with PD. It is thought that occurrence in this age is connected with genetic factors, mutations in e.g. PRKN, PINK1, DJ-1 and changes in proteins it is encoded. The loss of dopaminergic neurons in the nigrostriatal system leads to decreased dopamine (DA) concentrations. Pathogenic PD proteins may affect the DA level. The lower level of DA may be responsible for movement-related symptoms. EOPDs have a slower progression of the disease and a longer disorder duration but tend to develop dyskinesias and motor fluctuations earlier than LOPD. Currently, the diagnosis of PD is based on clinical criteria, supported neuroimaging like MRI or PET. Understanding the pathogenesis of the EOPD may be contributing to improving diagnostics and effectiveness of pharmacotherapy

Normal Aging and Dementia

Normal aging begins after 60 years of age. According to Harman, the accumulation of free radicals, which results from weakening of repair and protective mechanisms, takes place in the aging brain. It is believed that especially in the population of the most elderly there is increased incidence of both dementia and depression. The causes of these central nervous system disorders in the aging human body are changes at the molecular level, such as changes in the biochemical parameters, the accumulation of mutations in nuclear and mitochondrial DNA, and epigenetic changes. Biomarkers associated with aging of the brain include accumulated deposits of β-amyloid (Aβ), disturbed cholesterol homeostasis, altered neuroimaging parameters, and impaired glucose metabolism. Genetic factors are also responsible for normal aging, for example, SIRT1, AKT1, and CDKN1A, and among them the longevity genes, such as FOXO3A and CETP. Dementia as well as cognitive decline may be modified by poly-T variants of TOMM40 and APOE alleles via influencing the level of apolipoprotein E (apoE) in the brain and in the plasma as well as by its ability of Aβ clearance

Serotonin in Neurological Diseases

Serotonin (5-HT) is responsible for anxiety, aggression, and stress. Alterations in a serotonergic system play a significant role in pathogenesis of neurological diseases and neuropsychiatric disorders. A wide range of disturbances associated with serotonergic neurotransmission results from different functions of 5-HT in a nervous system. It is believed that 5-HT may be involved in the pathogenesis of migraine, epilepsy, Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), attention-deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). In these diseases, disturbances of 5-HT and its metabolites, such as 5-hydroxyindoleacetic acid (5-HIAA), were observed in the plasma, blood platelets, and cerebrospinal fluid (CSF). Changes in the level of this biogenic amine (5-HT) may be associated with malfunction of 5-HT receptors, reuptake transporter for 5-HT (5-HTT, SERT), the enzymes responsible for the synthesis and metabolism of 5-HT, and genetic variants for serotonergic system. It seems that 5-HT and its metabolites may be used as a diagnostic and prognostic marker for neurological diseases or a target for more efficient therapy in neurology in the future

Migraine and Risk Factors of Vascular Diseases

Migraine is a common neurological disease that affects both women and men in a different age. It is believed that migraine is a multifactorial disease with strong genetic and environmental factors. Current molecular studies in migraine are focused on biochemical (homocysteine, asymmetric dimethylarginine) and genetic (ACE, MTHFR, MTR, MTRR, CBS, eNOS, NOTCH3) risk factors associated with vascular diseases. Polymorphisms and mutations in mentioned genes predispose to migraine as well as cardiovascular diseases and stroke. According to the literature data, 13–15% of migraine with aura patients suffer from vascular diseases, too. The strict relation between migraine with aura and stroke is observed in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lifestyle plays an important role both in the pathomechanism of migraine and vascular diseases. Hypertension, obesity, dyslipidemia, and diabetes mellitus are the important risk factors for those pathological conditions. Therefore, early diagnosis of migraine and the implementing effective pharmacotherapy can lead to the prevention of cardiovascular and cerebrovascular diseases

Antiepileptic Drugs and Risk Factors of Vascular Diseases

Epilepsy is one of the most common neurological diseases, affecting approximately 1% of the population. It is a chronic disease and increased incidence falls in the period up to 1 year and 65 years of age. Most patients require long-term antiepileptic drugs (AEDs) therapy. In addition, approximately 30% of patients with epilepsy do not obtain satisfactory seizure control, which is defined as drug-resistant epilepsy. It is postulated that one of the causes of drug resistance can be polymorphisms of ABCB1/MDR1 gene, tested particularly in tumors. It is believed that the old generation of AEDs, e.g. CBZ, VPA, may change plasma Hcy, asymmetric dimethylarginine (ADMA) levels, disturb lipid levels, C-reactive protein, vitamins, markers of oxidative stress, which are risk factors for vascular and neurodegenerative diseases. Changes in the level of risk factors for vascular disease caused by enzymes inducing AEDs, CBZ, PB, and PHT lead to a small increase in the risk of myocardial infarction. Alteration of Hcy and ADMA levels are also linked to genetic factors, e.g. genetic variants of MTHFR, MTR, MTHFD1, CBS, DDAH1, eNOS genes. Individualization of treatment with AEDs and prevention against cardiovascular disease in patients with epilepsy may bring the best therapeutic effects in these patients