Khashayar Dashtipour

Ultrastructural features and synaptic connections of hilar ectopic granule cells in the rat dentate gyrus are different from those of granule cells in the granule cell layer.

Several investigators have shown the existence of dentate granule cells in ectopic locations within the hilus and molecular layer using both Golgi and retrograde tracing studies but the ultrastructural features and synaptic connections of ectopic granule cells were not previously examined. In the present study, the biocytin retrograde tracing technique was used to label ectopic granule cells following injections into stratum lucidum of CA3b of hippocampal slices obtained from epileptic rats. Electron microscopy was used to study hilar ectopic granule cells that were located 20-40 microm from the granule cell layer (GCL). They had ultrastructural features similar to those of granule cells in the GCL but showed differences, including nuclei that often displayed infoldings and thicker apical dendrites. At their origin, these dendrites were 6 microm in diameter and they tapered down to 2 microm at the border with the GCL. Both biocytin-labeled and unlabeled axon terminals formed exclusively asymmetric synapses with the somata and proximal dendrites of hilar ectopic granule cells. The mean number of axosomatic synapses for these cells was three times that for granule cells in the GCL. Together, these data indicate that hilar ectopic granule cells are postsynaptic to mossy fibers and have less inhibitory input on their somata and proximal dendrites than granule cells in the GCL. This finding is consistent with recent physiological results showing that hilar ectopic granule cells from epileptic rats are more hyperexcitable than granule cells in the GCL.

Expression of active caspase-3 in mitotic and postmitotic cells of the rat forebrain

Active caspase‐3 immunoreactivity was detected in the rat forebrain proliferative regions at birth and remained high in these areas for about 2 weeks, during which period labeled cells were present centroperipherally across the olfactory bulb. By the end of the third postnatal week, only a small number of immunolabeled cells remained in these forebrain structures. Active caspase‐3 immunolabeling was localized mostly to cell nuclei and co‐localized partially with TuJ1 and NeuN immunoreactivity, but not with glial fibrially acidic protein, OX‐42, γ‐aminobutyric acid, or terminal deoxynucleotidyl transferase‐mediated nick end labeling (TUNEL)‐positive labeling. Active caspase‐3 and 5‐bromo‐2′‐deoxyuridine (BrdU) double‐labeled nuclei were seen in the proliferative regions after 2 hours and in the periglomerular region of the bulb after 7 days following BrdU injections. Examination of the cells with electron microscopy confirmed that the active caspase‐3‐containing nuclei in the proliferative regions often had infoldings and appeared to be undergoing division. Some of the cells with active caspase‐3‐labeled nuclei in the bulb had synapses on their somata or dendrites. Labeled dendritic spines and a few axon terminals were also observed in the olfactory bulb. Taken together, it appears that a wave of active caspase‐3‐positive cells are dividing in the proliferative zones and then migrating to the bulb as they differentiate into neurons. Therefore, active caspase‐3 may play a role in cellular processes such as neuronal differentiation, migration, and plasticity, in addition to its role in cell death. J. Comp. Neurol. 433:4–22, 2001.

Diffusion, spread, and migration of botulinum toxin

Botulinum toxin (BoNT) is an acetylcholine release inhibitor and a neuromuscular blocking agent used for the treatment of a variety of neurologic and medical conditions. The efficacy and safety of BoNT depends on accurate selection and identification of intended targets but also may be determined by other factors, including physical spread of the molecule from the injection site, passive diffusion, and migration to distal sites via axonal or hematogenous transport. The passive kinetic dispersion of the toxin away from the injection site in a gradient‐dependent manner may also play a role in toxin spread. In addition to unique properties of the various BoNT products, volume and dilution may also influence local and systemic distribution of BoNT. Most of the local and remote complications of BoNT injections are thought to be due to unwanted spread or diffusion of the toxins biologic activity into adjacent and distal muscles. Despite widespread therapeutic and cosmetic use of BoNT over more than three decades, there is a remarkable paucity of published data on the mechanisms of distribution and its effects on clinical outcomes. The primary aim of this article is to critically review the available experimental and clinical literature and place it in the practical context.

Neuroplasticity in the damaged dentate gyrus of the epileptic brain.

Using Golgi preparations, Cajal described many cell types and connections of the dentate gyrus. He described granule cells as having a round or elliptical cell body with their long axis perpendicular to the granule cell layer, dendrites arising from one pole and an axon arising from the other. Cajal apparently never studied the brains from epileptic animals or humans, and thus did not report on changes in granule cell morphology after epilepsy. Several neuroplastic changes have been described in the dentate gyrus of epileptic mammals in the past decade or so using modern methods. Two changes involving their processes include mossy fiber sprouting of granule cell axons into the inner molecular layer of the dentate gyrus and the formation of hilar basal dendrites. Two changes associated with increased neurogenesis of granule cells in the epileptic brain include hilar ectopic granule cells and the dispersion of the granule cell layer. The significance of the first two changes is that granule cell axon collaterals establish additional synapses with apical and basal dendrites of granule cells, and these connections contribute to new recurrent excitatory circuitry. The significance of increased neurogenesis is that granule cells are migrating into inappropriate areas (deep hilus) or excessive numbers of granule cells accumulate in the layer (dispersion). These data on the epileptic dentate gyrus show that granule cells may change their axonal and dendritic arbors as well as their numbers and position to respond to altered activity possibly caused by decreased inhibition. These findings indicate that the dentate gyrus shows several neuroplastic changes following temporal lobe epilepsy.

Transdermal Rotigotine: A Clinically Innovative Dopamine-Receptor Agonist for the Management of Parkinson's Disease

Rotigotine is a highly lipophilic dopamine‐receptor agonist and the first transdermally delivered agent to demonstrate efficacy and safety as monotherapy in early Parkinsons disease and to reduce “off” hours in levodopa‐treated patients with advanced Parkinsons disease. The rotigotine pharmacophore is nonergolinic and demonstrates high affinity for dopamine D2 and D3 receptors. With once‐daily application, the patch matrix provides continuous, nonfluctuating plasma drug levels at steady state, resulting in continuous and steady plasma and brain levels and striatal dopamine‐receptor stimulation. In early Parkinsons disease, doses of rotigotine up to 8 mg/24 hours demonstrate comparable efficacy to ropinirole (at doses up to 12 mg/day); in advanced Parkinsons disease, doses of rotigotine up to 16 mg/24 hours demonstrate comparable efficacy and tolerability to pramipexole (at doses up to 4.5 mg/day). In the registration trials for early and advanced Parkinsons disease, the adverse effects most commonly observed with rotigotine were minor application site reactions, dizziness, nausea, and somnolence. Doses of transdermal rotigotine can be titrated to a maintenance dose within 2–3 weeks, and the once‐daily regimen minimizes complexity of therapy. The transdermal delivery system is also an advantage when nonoral administration is desired, and the 24‐hour, continuous, nonfluctuating drug levels can improve early morning and nocturnal symptoms of Parkinsons disease. Thus, transdermally delivered rotigotine is a clinically innovative and useful addition to the dopamine‐receptor agonist class. This review summarizes the key pharmacologic and clinical data for rotigotine and provides a focused clinical context for its use in early‐to‐advanced Parkinsons disease, as well as a brief summary for its role in restless legs syndrome.

Abo-, inco-, ona-, and rima-botulinum toxins in clinical therapy: a primer.

Botulinum neurotoxin (BoNT) is an acetylcholine release inhibitor and a neuromuscular‐blocking agent used for the treatment of a variety of medical and cosmetic indications. Currently, in the United States, there are four BoNT formulations licensed for use: abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, and rimabotulinumtoxinB. These revised name designations were established to reinforce the understanding that each BoNT product has an individual potency and is not interchangeable with any other BoNT product. The therapeutic use of BoNTs is expanding and new formulations are on the horizon. This article is a primer that describes distinctions among currently available, licensed BoNT formulations. Toxin pharmacology, product characteristics, storage, handling, preparation, and dosages will be reviewed. In addition, issues related to dose equivalency ratios, immunogenicity, potency, and toxin spread will be discussed. Therapeutic indications and safety are discussed briefly. Knowledge of the available and licensed BoNT formulations and the ability to make distinctions in toxin pharmacology, product characteristics, and indications are vital for product selection, preparation, drug information, avoidance of drug errors, quality assurance, and patient safety.

Effect of Exercise on Motor and Nonmotor Symptoms of Parkinson’s Disease

Background. Novel rehabilitation strategies have demonstrated potential benefits for motor and non-motor symptoms of Parkinsons disease (PD). Objective. To compare the effects of Lee Silverman Voice Therapy BIG (LSVT BIG therapy) versus a general exercise program (combined treadmill plus seated trunk and limb exercises) on motor and non-motor symptoms of PD. Methods. Eleven patients with early-mid stage PD participated in the prospective, double-blinded, randomized clinical trial. Both groups received 16 one-hour supervised training sessions over 4 weeks. Outcome measures included the Unified Parkinsons Disease Rating Scale (UPDRS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Modified Fatigue Impact Scale (MFIS). Five patients performed general exercise and six patients performed LSVT BIG therapy. Post-intervention evaluations were conducted at weeks 4, 12 and 24. Results. The combined cohort made improvements at all follow-up evaluations with statistical significance for UPDRS total and motor, BDI, and MFIS (P < 0.05). Conclusion. This study demonstrated positive effects of general exercise and LSVT BIG therapy on motor and non-motor symptoms of patients with PD. Our results suggest that general exercise may be as effective as LSVT BIG therapy on symptoms of PD for patients not able to readily access outpatient LSVT BIG therapy.

Iron Accumulation Is Not Homogenous among Patients with Parkinson’s Disease

Background. Iron is considered to lead to neurodegeneration and has been hypothesized as a possible cause of Parkinsons disease (PD). Susceptibility-weighted imaging (SWI) is a powerful tool to measure phase related iron content of brain. Methods. Twelve de novo patients with PD were recruited from the Movement Disorders Clinic, Department of Neurology, Loma Linda University. Twelve age- and sex-matched non-PD subjects were recruited from neurology clinic as controls. Using SWI, the phase related iron content was estimated from different brain regions of interest (ROIs). Results. There was a trend between increasing age and iron accumulation in the globus pallidus and putamen in all subjects. Iron accumulation was not significant in different ROIs in PD patients compared to controls after adjustment for age. Our data revealed heterogeneity of phase values in different brain ROIs among all subjects with an exaggerated trend at SN in PD patients. Conclusions. Our data suggest a nonhomogeneous pattern of iron accumulation in different brain regions among PD patients. Further studies are needed to explore whether this may correlate to the progression of PD. To our knowledge, this is the first study demonstrating the heterogeneity of iron accumulation in the brain, among patients with PD.

Sleep disturbances in Parkinson's disease with emphasis on rapid eye movement sleep behavior disorder.

ABSTRACT Sleep disturbances are common in patients with Parkinsons disease (PD). These disturbances can primarily affect the patients quality of life and may worsen the symptoms of PD. Among the multiple sleep disturbances in PD patients, there has been a marked growing interest in rapid eye movement (REM) sleep behavior disorder (RBD). This is likely due to the fact that RBD has been proven to precede the motor symptoms of PD by many years. The aim of this article is to examine the sleep disturbances found in PD, with special attention to RBD as a premotor symptom of PD, as well as to assess its proposed related pathophysiology. MEDLINE (1966–March 2010), American Academy of Sleep Medicines, The International Classification of Sleep Disorders, and current textbooks of sleep medicine were searched for relevant information. Search terms: RBD, sleep disturbances, Parkinsons disease, and pre-motor were used. Excessive daytime sleepiness (EDS), sleep attack, insomnia, restless leg syndrome (RLS), sleep-disordered breathing (SDB), and RBD are sleep disturbances commonly found in the literature related to PD. Sleep benefit has been proven to lessen PD motor symptoms. RBD has been described as a premotor symptom of PD in several prospective, retrospective, and cross-sectional studies. Sleep disturbances in PD can result secondarily to natural disease progression, as a side effect of the medications used in PD, or in result of pre-clinical pathology. Treatment of sleep disturbances in PD patients is crucial, as what is termed as, “sleep benefit effect” has been shown to improve the symptoms of PD.

Systematic literature review of abobotulinumtoxinA in clinical trials for adult upper limb spasticity.

Objective The aim of this study was to elucidate clinical trial efficacy, safety, and dosing practices of abobotulinumtoxinA (ABO) treatment in adult patients with upper limb spasticity (ULS). Methods A systematic literature review was performed to identify randomized controlled trials and other comparative clinical studies of ABO in the treatment of adult ULS published in English between January 1991 and January 2013. Medical literature databases (PubMed, Cochrane Library, and EMBASE) were searched, and a total of 295 records were identified. Of these, 12 primary publications that evaluated ABO for the management of ULS were included in the final data report. Synthesis Total ABO doses ranged between 500 and 1500 U for ULS. Most of the studies in ULS showed statistically significant benefits (reduction in muscle tone based on Ashworth score) of ABO vs. placebo. Statistical significance was reached for most evaluations of spasticity using the Modified Ashworth Scale. Statistically significant effects on active movement and pain were demonstrated, albeit less consistently. ABO was generally well tolerated across the individual studies; most adverse events reported were considered unrelated to treatment. Adverse events considered associated with ABO treatment included fatigue, tiredness, arm pain, skin rashes, flu-like symptoms, worsening of spasm, and weakness. Conclusions On the basis of data extracted from 12 randomized clinical studies, a strong evidence base (9/12 studies) exists for the use of ABO to reduce ULS caused by stroke.