Neuroprotective action and mechanistic evaluation of protodioscin against rat model of Parkinson’s disease

Background

Parkinson’s disease (PD) is the most widespread motor-affecting disease affecting majorly middle- and late age population. Thus, in the current study, we intended to explore the neuroprotective effect of protodioscin (Proto) against 6-hydroxydopamine (6-OHDA)-induced PD rat model.

Neurotoxic effects of berberine on long-term l-DOPA administration in 6-hydroxydopamine-lesioned rat model of Parkinson’s disease

The effects of berberine on long-term administration of l-DOPA in 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease (PD) were investigated. Rat models of PD were prepared by 6-OHDA lesions in the ipsilateral sides, and then were treated with berberine (5 and 15 mg/kg) and/or l-DOPA (10 mg/kg) once daily for 21 days. Treatments with either concentration of berberine (5 and 15 mg/kg) in 6-OHDA-lesioned groups decreased the numbers of tyrosine hydroxylase (TH)-immunopositive neurons in the substantia nigra and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum as compared to 6-OHDA-lesioned groups. In addition, dopaminergic neuronal cell death of the ipsilateral sides in 6-OHDA-lesioned groups was attenuated by l-DOPA administration. However, both concentrations of berberine in 6-OHDA-lesioned groups treated with l-DOPA aggravated the numbers of TH-immunopositive neurons in the substantia nigra and the levels of dopamine, norepinephrine, DOPAC and HVA in the striatum as compared to rats not treated with berberine. These results suggest that berberine leads to the degeneration of dopaminergic neuronal cells in the substantia nigra in the rat model of PD with chronic l-DOPA administration. Long-term l-DOPA therapy that may involve possibly neurotoxic isoquinoline agents including berberine should involve monitoring for adverse symptoms.     

Management of constipation in Parkinson’s disease

Introduction: Constipation is a frequent non-motor feature of Parkinson’s disease (PD). It is the most common gastrointestinal symptom of the disease and it can precede motor symptoms by as much as 20 years. Constipation can produce discomfort and affect activities of daily living, productivity and quality of life, thus warranting early diagnosis and treatment.

Areas covered: In this review, the safety and efficacy of traditional and novel strategies for constipation management will be discussed. A treatment algorithm for constipation in PD will be presented.

Expert opinion: Polyethylene glycol and lubiprostone are first-line compounds recommended by evidence-based medicine guidelines for the treatment of constipation due to slow colonic transit in PD. Management of constipation secondary to defecatory dysfunction due to pelvic floor dyssynergia can be done by levodopa or apomorphine injections, botulinum toxin type A injection into the puborectalis muscle, and nonpharmacological interventions, like biofeedback therapy or functional magnetic stimulation, which showed some benefit in PD patients with constipation, but in general more extensive studies are warranted.     

Neuroprotective effects of alkaloids from Piper longum in a MPTP-induced mouse model of Parkinson’s disease

Abstract

Context: Alkaloids of Piper longum L. (Piperaceae) (PLA) include piperine and piperlonguminine. Piper longum and piperine have multiple biological properties including antioxidant activity.

Objective: The present study investigated the neuroprotective effects of PLA in a MPTP-induced mouse model of Parkinson’s disease.

Materials and methods: PLA was prepared by extracting the dry seed of P. longum using 85% ethanol. Adult male C57BL/6 mice were divided into eight groups of 12 rats each. Experimental and control groups received an equivalent volume of saline, 0.5% CMC-Na, and 0.1% Tween 80, treated groups received oral PLA (30, 60, and 120?mg/kg), other groups treated with piperine (60?mg/kg) or Madopar (50?mg/kg). The PLA prevention group (PLA-Pr) administrated PLA (120?mg/kg) for 1 week before MPTP challenged. Except for the PLA-Pr group, others were treated for seven consecutive weeks. Parkinson’s disease was induced by injecting MPTP intraperitoneally (25?mg/kg) twice weekly for five consecutive weeks. Dopaminerigic (DA) neurons and their metabolism were detected by UFLC-MS/MS. Tyrosine hydroxylase (TH)-immunohistochemistry assay and Western blotting were performed. The antioxidant enzymatic levels were determined by kit-based assays.

Results: The LD₅₀ value of PLA was determined at 1509?mg/kg of body weight. PLA (60?mg/kg) can significantly increase total movement time and distance (p?<?0.05), increase levels of DA (p?<?0.05) and DOPAC (p?<?0.05), increase glutathione (GSH) level and superoxide dismutase (SOD) activity (p?<?0.05), and decrease the lipid peroxidation of malondiadehycle (MDA) (p?<?0.05) in PLA-treated groups as compared with the control group.

Discussion and conclusion: Our results indicate that PLA possesses neuroprotective effects and has ameliorative properties in dopaminergic neurons.     

In vivo administration of VEGF- and GDNF-releasing biodegradable polymeric microspheres in a severe lesion model of Parkinson’s disease

In this work, the neuroregenerative potentials of microencapsulated VEGF, GDNF and their combination on a severely lesioned rat model were compared with the aim of developing a new strategy to treat advanced stages of Parkinson’s disease. Both neurotrophic factors were separately encapsulated into polymeric microspheres (MSs) to obtain a continuous drug release over time. The regenerative effects of these growth factors were evaluated using a rotation behaviour test and quantified by the number of surviving TH + cells. The biological activities of encapsulated vascular endothelial growth factor (VEGF) and glial cell line-derived neurotrophic factor (GDNF) were investigated in HUVEC and PC12 cells, respectively. The treatment of 6-OHDA-lesioned rats with GDNF microspheres and with both VEGF and GDNF microspheres resulted in improved results in the rotation behaviour test. Both groups also showed higher levels of neuroregeneration/neuroreparation in the substantia nigra than the control group did. These results were confirmed by the pronounced TH + neuron recovery in the group receiving VEGF + GDNF-MS, demonstrating regenerative effects.     

Ascorbic acid ameliorates behavioural deficits and neuropathological alterations in rat model of Alzheimer’s disease

Exploring the links between neural pathobiology and behavioural deficits in Alzheimer’s disease (AD), and investigating substances with known therapeutic advantages over subcellular mechanisms underlying these dysfunctions could advance the development of potent therapeutic molecules for AD treatment. Here we investigated the efficacy of ascorbic acid (AA) in reversing aluminium chloride (AlCl₃)-induced behavioural deficits and neurotoxic cascades within prefrontal cortex (PFC) and hippocampus of rats. A group of rats administered oral AlCl₃ (100 mg/kg) daily for 15 days showed degenerative changes characterised by significant weight loss, reduced exploratory/working memory, frontal-dependent motor deficits, cognitive decline, memory dysfunction and anxiety during behavioural assessments compared to control. Subsequent analysis showed that oxidative impairment-indicated by depleted superoxide dismutase and lipid peroxidation (related to glutathione-S-transferase activity), cholinergic deficits seen by increased neural acetylcholinesterase (AChE) expression and elevated lactate dehydrogenase underlie behavioural alterations. Furthermore, evidences of proteolysis were seen by reduced Nissl profiles in neuronal axons and dendrites which correspond to apoptotic changes observed in H&E staining of PFC and hippocampal sections. Interestingly, AA (100 mg/kg daily for 15 days) significantly attenuated behavioural deficits in rats through inhibition of molecular and cellular stressor proteins activated by AlCl_3. Our results showed that the primary mechanisms underlying AA therapeutic advantages relates closely with its abilities to scavenge free radicals, prevent membrane lipid peroxidation, modulate neuronal bioenergetics, act as AChE inhibitor and through its anti-proteolytic properties. These findings suggest that supplementing endogenous AA capacity through its pharmacological intake may inhibit progression of AD-related neurodegenerative processes and behavioural alterations.     

Rasagiline in the pharmacotherapy of Parkinson’s disease – a review

Despite the current efficacious symptomatic approaches, the search is on for new therapies for Parkinson’s disease that can control the cardinal symptoms of the disease (tremor, rigidity and bradykinesia), control/prevent motor complications induced by long-term levodopa, act on non-motor disease symptoms (dementia, dysautonomia, pain, insomnia, falls) and halt disease progression. Rasagiline is a monoamine oxidase-B inhibitor that has demonstrated efficacy against the cardinal symptoms of Parkinson’s disease when used as monotherapy in early Parkinson’s disease, and as an adjunct to levodopa in advanced disease stages. It reduces the duration and severity of poor symptom response episodes in fluctuating patients. Preliminary results allow discussion of putative effects of rasagiline on some non-motor signs and disease progression. This article outlines the evidence surrounding the efficacy and safety of rasagiline, and discusses its potential to address some of the currently unmet needs of Parkinson’s disease therapy.     

Nigral and ventral tegmental area lesioning induces testicular and sperm morphological abnormalities in a rotenone model of Parkinson’s disease

Although sexual health is affected by Parkinson’s disease (PD), the effect on testicular health and/or sperm quality is not well discussed. After 21 days of rotenone lesioning, we observed dopaminergic neuronal degeneration in the substantia nigra and hypothalamus. There were minimal SPACA-1-expressing epididymal spermatozoa with morphological abnormalities, scanty luminal spermatozoa and reduced testicular spermatids and post-meiotic germ cells indicating hypospermatogenesis. Occludin-expressing sertoli cells were dispersed over a wide area indicating compromised blood-testes barrier. Activated caspase-3 expression was intense while immunoreactivity of spermatogenic-enhancing SRY and GADD45 g was weak. Although serum follicle stimulating hormone level was not affected, the lesion was associated with reduced serum testosterone level, testicular oxidative damage and inhibition of acetylcholinesterase activity, even when rotenone was not detected in the testes. Together, dopaminergic lesions may mediate testicular and sperm abnormalities via the brain-hypothalamic-testicular circuit independent of the pituitary, thereby establishing a causal link between Parkinsonism and reproductive dysfunction.     

Advances in understanding genomic markers and pharmacogenetics of Parkinson’s disease

Introduction: The inheritance pattern of Parkinson’s disease (PD) is likely multifactorial (owing to the interplay of genetic predisposition and environmental factors). Many pharmacogenetic studies have tried to establish a possible role of candidate genes in PD risk. Several studies have focused on the influence of genes in the response to antiparkinsonian drugs and in the risk of developing side-effects of these drugs.

Areas covered: This review presents an overview of current knowledge, with particular emphasis on the most recent advances, both in case-control association studies on the role of candidate genes in the risk for PD as well as pharmacogenetic studies on the role of genes in the development of side effects of antiparkinsonian drugs. The most reliable results should be derived from meta-analyses of case-control association studies on candidate genes involving large series of PD patients and controls, and from genome-wide association studies (GWAS).

Expert opinion: Prospective studies of large samples involving several genes with a detailed history of exposure to environmental factors in the same cohort of subjects, should be useful to clarify the role of genes in the risk for PD. The results of studies on the role of genes in the development of side-effects of antiparkinsonian drugs should, at this stage, only be considered preliminary.     

Dopaminergic substitution in Parkinson’s disease

Motor complications associated with long-term levodopa application, which follow the so-called honeymoon period of well-tolerated levodopa administration and are looked upon as one clinical marker for progression of Parkinson’s disease (PD), initiated a long and controversial debate on the putative neurotoxicity of levodopa. Since dopamine agonists (DA) delay onset of motor complications, they support the neuroprotective treatment strategy in PD. Efficacy and tolerability of DA differs in particular due to their affinity to various dopamine receptor subtypes. The accumulating evidence for levodopa-associated homocysteinaemia, which represents a risk factor for increased incidence of vascular disease in PD, supports the strategy of initial DA application and the use of levodopa as an add-on compound in as low a dose as possible in young PD patients.     

Dopamine agonists in Parkinson’s disease

Levodopa (LD), the immediate precursor of dopamine, is the most effective agent in the treatment of Parkinson’s disease (PD). While quite successful in treating the primary motor deficits of PD, most patients eventually develop LD-related motor fluctuation, dyskinesias and other adverse effects associated with chronic LD therapy. There is also concern that LD is neurotoxic, although this has not been demonstrated in any in vivo studies. Dopamine agonists (DAs) have been shown to be about as effective as LD in symptomatic treatment of mild-to-moderate PD. In addition, there is a lower tendency to develop motor fluctuations and dyskinesias with DA treatment than after initiation of therapy with LD. Furthermore, there is preclinical and clinical data to suggest a slowing of neurodegeneration with DAs. The adverse effects of DAs are similar to those experienced with LD, except that the ergot agents are associated with a small risk of tissue fibrosis not noted with the non-ergot DAs.     

New and emerging medical therapies in Parkinson’s disease

Introduction: Parkinson’s disease (PD) is one of the most challenging neurodegenerative disorders to treat as it manifests with a large variety of troublesome, and often disabling, motor and non-motor symptoms. Despite limitations, such as motor and other complications, levodopa remains the most effective drug in the treatment of PD.

Areas covered: In this review, we focus on phase 2 and 3 studies describing new and emerging medical therapies in PD. We discuss new formulations of levodopa, medications that prolong levodopa response and ameliorate levodopa-induced dyskinesias, and innovative delivery methods that are currently being evaluated in clinical trials or are in development with the promise of better efficacy and tolerability. We also describe novel non-dopaminergic drugs that have been identified for treatment of motor and non-motor symptoms. A specific section is designated for potential disease modifying therapies.

Expert Opinion: Alternative formulations of levodopa appear to be promising especially to help with the motor fluctuations either by providing sustained benefits with controlled released formulations or ameliorate sudden OFF by formulations such as inhaled levodopa. Several different medications affecting non-dopaminergic pathways are being evaluated which may aide levodopa. As the understanding of the disease grows further, numerous novel neuroprotective or disease modifying therapies have been suggested. This along with development of medications to treat various non-motor symptoms will help improve quality of life of patients with PD.     

Protective and therapeutic activity of honokiol in reversing motor deficits and neuronal degeneration in the mouse model of Parkinson’s disease

Background

Parkinson’s disease (PD) is a progressive and profound movement disorder resulting from neurodegeneration in the nigrostriatal dopaminergic system, but current treatment neither cures nor stops PD from advancing. Based on the ability to suppress oxidative stress, excitotoxicity, and neuroinflammation, the potential of honokiol as a novel neuroprotective agent for PD treatment was determined.

Recent important trials of pharmacotherapy in Parkinson’s disease

Parkinson’s disease (PD) affects ~ 1% of individuals > 60 years. Of these PD patients ～ 40% suffer dementia in later life. Levodopa is commonly used in the treatment of PD. Experimental evidence suggests that the dopamine synthesised from levodopa may contribute to the further degeneration of dopaminergic neurons. The results of the clinical outcome part of the Earlier Versus Later Levodopa Therapy in PD study suggest that levodopa slows the progression of PD. In contrast, the single photon emission-computed tomography imaging substudy was not conclusive but suggested that levodopa hastened the progression of PD. Thus, further studies of the effects of levodopa on the progression of PD are needed before it can be proved that levodopa does not have a detrimental effect on dopaminergic neurons. In a clinical trial of the anticholinesterase rivastigmine, a small improvement was observed in some patients suffering from dementia associated with PD. This small benefit has to be balanced against cholinergic side effects and a possible loss of efficacy of antimuscarinic agents used for motor control in PD.     

Drug treatment of non-motor symptoms in Parkinson’s disease

Non-motor symptoms may considerably reduce parkinsonian quality of life, particularly in advanced stages of the disease. Autonomic features, such as seborrhoea, hyperhidrosis, orthostatic hypotension, excessive salivation, bladder dysfunction and GI disturbances, and neuropsychiatric symptoms, such as depression, sleep disorders, psychosis and dementia, appear in the course of Parkinson’s disease. Pharmacotherapy of these non-motor symptoms complicates long-term antiparkinsonian combination drug therapy due to possible drug interactions, side effects and changes in metabolism. Moreover, antiparkinsonian compounds themselves contribute to the onset of these non-motor symptoms to a considerable extent. This complicates differentiation between the disease process itself and drug-related effects, thus influencing therapeutic options, which are often limited because of comorbidity and polypharmacy. Therefore, standardised recommendations are questionable, since drug tolerability and response differ between patients. Nevertheless, this review tries to provide a survey of possible therapeutic options for the treatment of the symptoms of Parkinson’s disease other the dopamine-sensitive motor features.     

Neuroprotection by marine-derived compound, 11-dehydrosinulariolide, in an in vitro Parkinson’s model: a promising candidate for the treatment of Parkinson’s disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by tremor, rigidity, bradykinesia, and gait impairment. So far, very few pharmacological agents have been isolated or developed that effectively inhibit the progression of PD. However, several studies have demonstrated that inflammatory processes play critical roles in PD. Therefore, anti-inflammatory agents may suppress disease progression in PD. 11-Dehydrosinulariolide was isolated from cultured soft corals. The anti-inflammatory effect of this molecule has been observed through suppression of the expression of two main pro-inflammatory proteins: inducible nitric oxide synthase and cyclooxygenase-2, in lipopolysaccharide-stimulated macrophage cells. We also found that 11-dehydrosinulariolide significantly reduced 6-hydroxydopamine (6-OHDA)-induced cytotoxicity and apoptosis in a human neuroblastoma cell line (SH-SY5Y). The pharmacological activity of this compound has been studied, and it is associated with the inhibition of 6-OHDA-induced activation of caspase-3 and translocation of nuclear factor kappa B. 11-Dehydrosinulariolide increased the activation of survival-signaling phospho-Akt but not phospho-ERK. The neuroprotective effect of 11-dehydrosinulariolide was assessed here using 6-OHDA-treated SH-SY5Y cells, wherein neuroprotection is mediated through regulation of phosphatidylinositol 3-kinase (PI3K). Furthermore, 11-dehydrosinulariolide caused a significant decrease in caspase-3/7 activity in comparison to the 6-OHDA-treated group, indicating that 11-dehydrosinulariolide has neuroprotective properties. We conclude that 11-dehydrosinulariolide is a promising candidate for the treatment of Parkinson's disease through its anti-apoptotic and anti-inflammatory action via PI3K signaling.     

Established therapies and novel targets in the treatment of Parkinson’s disease

Parkinson’s disease affects more than 1% of individuals older than 60 years of age. The gold standard of its symptomatic treatment is levodopa therapy, which in time leads to motor fluctuations and dyskinesia due to noncontinuous receptor stimulation. Dopamine agonists and monoamine oxidase-B inhibitors are recommended as initial therapy, but they are less effective in the advanced stages of the disease. Treatment should be individualized for the patient, dependent on the stage, with attention to nonmotor symptoms. No effective neuroprotective therapy for Parkinson’s disease is yet available, and there is currently substantial interest in the development of new nondopaminergic agents. Analogs of kynurenic acid and inhibitors of the enzymes involved in the synthesis of quinolinic acid may exert a neuroprotective effect.