Commentary

Radioligands of the vesicular monoamine transporter and their use as markers of monoamine storage vesicles

• L-

  menthol (LM) is a safe and bioactive monoterpenoid from Mentha haplocalyxBriq., with which an acute treatment has shown significant antidepressant-like effects potentially mediated by the modification of monoamine system in mice. Nonetheless, the above conclusions were all based on the forced swimming test. The antidepressant-like effects of acute and subchronic administrations with LM on other depression models have never been illuminated, and its potential mechanisms require further explorations. In this study, the antidepressant-like effects and potential mechanisms of an acute treatment with LM were validated through behavioral despair tests, reserpine-induced ptosis, akinesia and hypothermia test, and 5-hydroxytryptophan-induced head-twitch test in mice. The antidepressant-like effects of subchronic treatments with LM were evaluated in a modified lipopolysaccharide (LPS)-induced depression model. Furthermore, the effects of subchronic treatments with LM on the microglial activation, hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling pathway in LPS-induced mice were detected through immunofluorescence assay, enzyme-linked immunosorbent assay and western blotting analysis. Our results showed that acute and subchronic administrations with LM exerted significant antidepressant-like effects in different depression models, which might be mediated by modulating the monoamine system, alleviating neuroinflammation and upregulating the BDNF/TrkB signaling pathway in mice. Taken together, the current study systematically explored the potential of LM as a new candidate for depression therapy, and provided a modified LPS-induced depression model with better apparent and predictive validity.

Dysregulation of striatal dopamine is considered to be an important driver of pathophysiological processes in schizophrenia. Despite being one of the main origins of dopaminergic input to the striatum, the (dys)functioning of the substantia nigra (SN) has been relatively understudied in schizophrenia. Hence, this paper aims to review different molecular aspects of nigral functioning in patients with schizophrenia compared to healthy controls by integrating post-mortem and molecular imaging studies. We found evidence for hyperdopaminergic functioning in the SN of patients with schizophrenia (i.e. increased AADC activity in antipsychotic-free/-naïve patients and elevated neuromelanin accumulation). Reduced GABAergic inhibition (i.e. decreased density of GABAergic synapses, lower VGAT mRNA levels and lower mRNA levels for GABA_A receptor subunits), excessive glutamatergic excitation (i.e. increased NR1 and Glur5 mRNA levels and a reduced number of astrocytes), and several other disturbances implicating the SN (i.e. immune functioning and copper concentrations) could potentially underlie this nigral hyperactivity and associated striatal hyperdopaminergic functioning in schizophrenia. These results highlight the importance of the SN in schizophrenia pathology and suggest that some aspects of molecular functioning in the SN could potentially be used as treatment targets or biomarkers.

Parkinson's disease (PD) is a neurodegenerative condition characterized by the dopamine (DA) neuronal loss in the substantia nigra. PD impairs motor controls symptoms such as tremor, rigidity, bradykinesia and postural imbalance gradually along with non-motor problems such as olfactory dysfunction, constipation, sleeping disorder. Though surplus of factors and mechanisms have been recognized, the precise PD etiopathogenesis is not yet implied. Reports suggest that various environmental factors play a crucial role in the causality of the PD cases. Epidemiological studies have reported that heavy metals has a role in causing defects in substantia nigra region of brain in PD. Though the reason is unknown, exposure to heavy metals is reported to be an underlying factor in PD development. Metals are classified as either essential or non-essential, and they have a role in physiological processes such protein modification, electron transport, oxygen transport, redox reactions, and cell adhesion. Excessive metal levels cause oxidative stress, protein misfolding, mitochondrial malfunction, autophagy dysregulation, and apoptosis, among other things. In this review, we check out the link between heavy metals like copper (Cu), arsenic (As), cadmium (Cd), iron (Fe), and lithium (Li) in neurodegeneration, and how it impacts the pathological conditions of PD. In conclusion, increase or decrease in heavy metals involve in regulation of neuronal functions that have an impact on neurodegeneration process. Through this review, we suggest that more research is needed in this stream to bring more novel approaches for either disease modelling or therapeutics.

Radiotracers along with single photon emission computed tomography (SPECT) and positron emission computed tomography (PET) instruments have led to significant advances in the knowledge of the neurobiology and pathophysiology of neurodegenerative diseases such as Parkinson's disease (PD), clinical diagnosis and patient care. Valuable information is available on both pathology and progression of the neurodegenerative disease through human brain imaging. Preliminary data from PET and SPECT studies in early PD suggests that dopamine agonists might have a slight neuroprotective effect. They also might slow down the rate of progression of the disease. This review gives an overview of the recent SPECT and PET imaging radiotracers of the dopaminergic system imaging used in order for differential diagnosis and for the determination of the progression rate of PD.

Fibromyalgia (FM) is a musculoskeletal chronic pain syndrome. Its prevalence in women is higher than in men possibly by hormonal factors given that symptoms are aggravated during sex hormone-related events, such as the premenstrual period, pregnancy, postpartum or menopause. The aim of the present study was to investigate whether hyperalgesia and allodynia, in reserpine-induced experimental FM, depend on sex, estrous cycle, ovariectomy and replacement with 17β-estradiol. To fulfill this objective, we compared males, intact females with known estrous cycle phases and ovariectomized (OVX) rats treated with 17β-estradiol. Data demonstrated that reserpine administration disrupted the normal estrous cycle and produced that all females entered metestrus/diestrus. In addition, this treatment leads to muscle hyperalgesia and tactile allodynia in a similar manner in male and intact female rats. However, the absence of ovarian hormones (in OVX rats) increased muscle nociception. 17β-estradiol (2.5–10 μg/rat) produced antihyperalgesic and antiallodynic effects 24 h, but not 8 h, after its administration, suggesting a genomic mechanism. The present results support the validity of the reserpine-induced FM model for searching alternatives of treatment, particularly during endocrine phases when pain is exacerbated such as menopause, and that 17β-estradiol replacement might be useful.

Depression is a debilitating psychiatric condition that remains the second most common cause of disability worldwide. Currently, depression affects more than 4 per cent of the world’s population. Most of the drugs intended for clinical management of depression augment the availability of neurotransmitters at the synapse by inhibiting their neuronal reuptake. However, the therapeutic efficacy of antidepressants is often compromised as they are unable to reach brain by the conventional routes of administration. The purpose of the present study was to reconnoiter the potential of mucoadhesive PLGA-chitosan nanoparticles for the delivery of encapsulated Desvenlafaxine to the brain by nose to brain delivery route for superior pharmacokinetic and pharmacodynamic profile of Desvenlafaxine. Desvenlafaxine loaded PLGA-chitosan nanoparticles were prepared by solvent emulsion evaporation technique and optimized for various physiochemical characteristics. The antidepressant efficacy of optimized Desvenlafaxine was evaluated in various rodent depression models together with the biochemical estimation of monoamines in their brain. Further, the levels of Desvenlafaxine in brain and blood plasma were determined at various time intervals for calculation of different pharmacokinetic parameters. The optimized Desvenlafaxine loaded PLGA-chitosan nanoparticles (∼172 nm/+35 mV) on intranasal administration significantly reduced the symptoms of depression and enhanced the level of monoamines in the brain in comparison with orally administered Desvenlafaxine. Nose to brain delivery of Desvenlafaxine PLGA-chitosan nanoparticles also enhanced the pharmacokinetic profile of Desvenlafaxine in brain together with their brain/blood ratio at different time points. Thus, intranasal mucoadhesive Desvenlafaxine PLGA-chitosan nanoparticles could be potentially used for the treatment of depression.