Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus.

Basal ganglia (BG) circuits orchestrate complex motor behaviors predominantly via inhibitory synaptic outputs. Although these inhibitory BG outputs are known to reduce the excitability of postsynaptic target neurons, precisely how this change impairs motor performance remains poorly understood. Here, we show that optogenetic photostimulation of inhibitory BG inputs from the globus pallidus induces a surge of action potentials in the ventrolateral thalamic (VL) neurons and muscle contractions during the post-inhibitory period. Reduction of the neuronal population with this post-inhibitory rebound firing by knockout of T-type Ca2+ channels or photoinhibition abolishes multiple motor responses induced by the inhibitory BG input. In a low dopamine state, the number of VL neurons showing post-inhibitory firing increases, while reducing the number of active VL neurons via photoinhibition of BG input, effectively prevents Parkinson disease (PD)-like motor symptoms. Thus, BG inhibitory input generates excitatory motor signals in the thalamus and, in excess, promotes PD-like motor abnormalities. VIDEO ABSTRACT.

Pediatric psychopharmacology and local anesthesia: potential adverse drug reactions with vasoconstrictor use in dental practice.

Pain management is important when dealing with pediatric dental patients. The use of local anesthetics can be especially challenging for children taking psychotropic medications. The purpose of this paper was to identify pertinent information regarding drug interactions between vasoconstrictor/local anesthetic combinations and medications for the management of psychiatric or behavior disorders in children. Many of the reported interactions are controversial, largely theoretical with very limited clinical evidence, and not well defined. However, when considering the potential for significant increased blood pressure when local anesthesia containing a vasoconstrictor is used, a thorough under standing of the pharmacological actions of medications used to treat psychiatric or behavioral disorders and vasoconstrictors can help dental professionals minimize the potential risk of drug interactions in their practice.

Protective effects of geraniol (a monoterpene) in a diabetic neuropathy rat model: attenuation of behavioral impairments and biochemical perturbations.

Involvement of oxidative stress, inflammatory response, and mitochondrial dysfunction in the development of diabetic neuropathy (DN) is well appreciated. The present study examines the potential of geraniol (GE), a well-known phytoconstituent commonly found in lemon, spices, rose oil, etc., to attenuate DN-associated oxidative/nitrosative stress by employing a streptozotocin (STZ) diabetic rat model. STZ-induced diabetic rats provided with oral supplements of GE (100 mg/kg bw/day, 8 weeks) exhibited significant improvement in tail-flick latency (sensory function) and the narrow beam test (motor function). Terminally, elevated levels of oxidative markers (reactive oxygen species, malondialdehyde, hydroperoxides) in cytosol of the sciatic nerve (SN) and in selected regions of the brain of diabetic rats were markedly reduced by GE supplements. Furthermore, GE significantly diminished the levels of protein carbonyls (a measure of protein oxidation) and nitrites in diabetic rats. In addition, in mitochondria, GE supplements restored the activities of enzymes, such as complexes I-III, succinate dehydrogenase, and citrate synthase, in brain regions of diabetic rats, with a concomitant reduction in the levels of oxidative markers. GE significantly lowered the enhanced cytosolic calcium levels and acetylcholinesterase activity in the SN and the brain regions of diabetic rats. Depleted dopamine levels evident in the SN and the cortex/striatum among diabetic rats were restored by GE. From our data, we hypothesize that GE may be a promising therapeutic candidate in the management of DN in humans. Further understanding of the molecular mechanisms of its neuromodulatory effects is essential in order to exploit its therapeutic efficacy.

Liposomal-formulated curcumin [Lipocurc™] targeting HDAC (histone deacetylase) prevents apoptosis and improves motor deficits in Park 7 (DJ-1)-knockout rat model of Parkinson's disease: implications for epigenetics-based nanotechnology-driven drug platform.

BACKGROUND: Converging evidence suggests dysregulation of epigenetics in terms of histone-mediated acetylation/deacetylation imbalance in Parkinson's disease (PD). Targeting histone deacetylase (HDAC) in neuronal survival and neuroprotection may be beneficial in the treatment and prevention of neurodegenerative disorders. Few pharmacological studies use the transgenic model of PD to characterize the neuroprotection actions of a lead compound known to target HDAC in the brain. METHODS: In our study, we investigated neuroprotective effects of liposomal-formulated curcumin: Lipocurc™ targeting HDAC inhibitor in the DJ-1(Park 7)-gene knockout rat model of PD. Group I (DJ-1-KO-Lipocurc™) received Lipocurc™ 20 mg/kg iv 3× weekly for 8 weeks; Group II: DJ-1 KO controls (DJ-1 KO-PBS) received i.v. phosphate-buffered saline (PBS). Group III: DJ-1-Wild Type (DJ-1 WT-PBS) received PBS. We monitored various components of motor behavior, rotarod, dyskinesia, and open-field behaviors, both at baseline and at regular intervals. Toward the end of the 8 weeks, we measured neuronal apoptosis and dopamine (DA) neuron-specific tyrosine hydroxylase levels by immunohistochemistry methods at post-mortem. RESULTS: We found that DJ-KO Group I and Group II, as compared with DJ-1 WT group, exhibited moderate degree of motor impairment on the rotarod test. Lipocurc™ treatment improved the motor behavior motor impairment to a greater extent than the PBS treatment. There was marked apoptosis in the DJ-1 WT group. Lipocurc™ significantly blocked neuronal apoptosis: the apoptotic index of DJ-1-KO-Lipocurc™ group was markedly reduced compared with the DJ-KO-PBS group (3.3 vs 25.0, p<0.001). We found preliminary evidence Lipocurc™ stimulated DA neurons in the substantia nigra. The ratio of immature to mature DA neurons in substantia nigra was statistically higher in the DJ-1-KO-Lipocurc™ group (p<0.025). CONCLUSIONS: We demonstrated for the first time Lipocurc™'s anti-apoptotic and neurotrophic effects in theDJ-1-KO rat model of PD. Our promising findings warrant randomized controlled trial of Lipocurc™ in translating the novel nanotechnology-based epigenetics-driven drug discovery platform toward efficacious therapeutics in PD.

Gitelman syndrome as a cause of psychomotor retardation in a toddler.

INTRODUCTION: Gitelman syndrome (GS) is a very rare autosomal recessive tubulopathy due to loss-of-function or mutation in solute carrier family12, member 3 gene (SLC12A3 gene) encoding thiazide-sensitive NaCl co-transporter in the distal convoluted tubule, leading to hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria and low-to-normal blood pressure. Clinical signs are mostly secondary to chronic hypokalemia and include dizziness, fatigue, constipation and weakness. Patients can also present with muscle cramps, tetany, fatigue and convulsions due to severe metabolic alkalosis or hypomagnesemia. Manifestations of GS are rarely apparent before the age of five, and the syndrome is usually diagnosed during adolescence or adulthood. Here we describe a case of GS presenting in infancy with hypokalemia and psychomotor retardation. CASE REPORT: We present an 18-month-old boy who presented with psychomotor retardation and failure to thrive. Investigations revealed hypokalemia at 2.7 mmol/L, metabolic alkalosis, hypocalciuria and normal serum magnesium level. The diagnoses of Barter syndrome (BS) and Gitelman syndrome (GS) were considered. Genetic studies confirmed the diagnosis of GS and three different mutations of in SLC12A3 gene were detected. Two mutations (c.2576T>C and c.2929C>Ty) were considered as causal ones, with the patient´s parents being the heterozygous carriers. Oral potassium supplementation resulted in normalisation of the hypokalemia and psychomotor improvement. CONCLUSION: We report a rare case of psychomotor retardation occurring at an early age in genetically confirmed GS. In spite of being a rare disorder, GS has to be considered in children with developmental delay and muscle weakness. With adequate treatment, GS patients have an excellent prognosis.

Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage.

T-lymphocytes promote cerebral inflammation, thus aggravating neuronal injury after stroke. Fingolimod, a sphingosine 1-phosphate receptor analog, prevents the egress of lymphocytes from primary and secondary lymphoid organs. Based on these findings, we hypothesized fingolimod treatment would reduce the number of T-lymphocytes migrating into the brain, thereby ameliorating cerebral inflammation following experimental intracerebral hemorrhage (ICH). We investigated the effects of fingolimod in two well-established murine models of ICH, implementing intrastriatal infusions of either bacterial collagenase (cICH) or autologous blood (bICH). Furthermore, we tested the long term neurological improvements by Fingolimod in a collagenase-induced rat model of ICH. Fingolimod, in contrast to vehicle administration alone, improved neurological functions and reduced brain edema at 24 and 72 h following experimental ICH in CD-1 mice (n=103; p<0.05). Significantly fewer lymphocytes were found in blood and brain samples of treated animals when compared to the vehicle group (p<0.05). Moreover, fingolimod treatment significantly reduced the expression of intercellular adhesion molecule-1 (ICAM-1), interferon-γ (INF-γ), and interleukin-17 (IL-17) in the mouse brain at 72 h post-cICH (p<0.05 compared to vehicle). Long-term neurocognitive performance and histopathological analysis were evaluated in Sprague-Dawley rats between 8 and 10 weeks post-cICH (n=28). Treated rats showed reduced spatial and motor learning deficits, along with significantly reduced brain atrophy and neuronal cell loss within the basal ganglia (p<0.05 compared to vehicle). We conclude that fingolimod treatment ameliorated cerebral inflammation, at least to some extent, by reducing the availability and subsequent brain infiltration of T-lymphocytes, which improved the short and long-term sequelae after experimental ICH in rodents.

Azadirachta indica mitigates behavioral impairments, oxidative damage, histological alterations and apoptosis in focal cerebral ischemia-reperfusion model of rats.

Azadirachta indica Linn. (Meliaceae) has been used from ancient times as a remedy for various ailments. The present study was designed to investigate the antioxidant and anti-apoptotic properties of A. indica seed extract (ASE) in transient middle cerebral artery occlusion (MCAO) rat model. Antioxidant potential of ASE was determined in vitro. Further, ASE was evaluated against neurological deficits, histological alterations (TTC, CV and H&E) and oxidative damage (TBARS, GSH and nitrite) in MCAO rats. Moreover, caspase-3 and -9 were analyzed to evaluate the anti-apoptotic activity of ASE. ASE has shown potent in vitro reducing power (126.2 mg AsAE/g extract) and free radical scavenging activities (DPPH 171.0 and NO 176.0 µg/ml). Furthermore, ASE inhibited oxidative stress and decreased the activities of caspase-3 (26.7 %, p < 0.05) and caspase-9 (31.2 %, p < 0.01) thus, reduced neuronal loss in MCAO rats. Our data revealed that ASE has potent antioxidant and anti-apoptotic properties, and may be explored for its active constituents against neurodegenerative diseases.

Children and adolescents with severe mental illness need vitamin D supplementation regardless of disease or treatment.

BACKGROUND: To protect against osteoporosis, keeping the vitamin D blood level (25[OH]D; VDBL) above 30 ng/mL is recommended. It is established that regular intake of vitamin D, calcium intake, and physical exercise contribute to maximizing bone mineral mass during childhood and adolescence. Recent articles suggest that patients with schizophrenia treated with antipsychotics have low VDBL and may have a higher risk of hip fractures in their later years than the general population. OBJECTIVES: To evaluate whether adolescent psychiatric inpatient VDBL is lower than the 30-ng/mL optimal threshold and to document low-VDBL risk factors. METHOD: We determined the VDBL of all consecutive inpatients from three adolescents units in 2009 (N = 136). Univariate analyses explored the influence on VDBL of (1) well-documented risk factors (e.g., age, gender, ethnic origin, body mass index, or season) and (2) suspected risk factors (e.g., disease type or antipsychotic treatment). RESULTS: All but six patients had a VDBL <30 ng/mL (mean [ ± SD]: 15.9 [ ± 8.4] ng/mL). VDBL was significantly lower for all patients during the first quarter of the year compared to the other three (all p < 0.01). VDBL was also lower for blacks/North Africans 12.8 (±7.0) than for Caucasians/Europeans 17.2 (±8.5): t = 2.62, p = 0.009. We found no differences between patients regarding disease category (K = 3.75, p = 0.154) or antipsychotic treatment (t = 0.127, df = 124, p = 0.89). CONCLUSION: VDBL in an adolescent population with severe mental illness is lower than current recommendations of optimal level for bone health regardless of treatment or disease type. Because adolescence is a period of bone construction and could represent a critical window of opportunity for maximizing bone mass, especially among patients with severe mental illness, we recommend vitamin D supplementation.

Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms.

Severe vitamin B(12) deficiency produces a cluster of neurological symptoms in infants, including irritability, failure to thrive, apathy, anorexia, and developmental regression, which respond remarkably rapidly to supplementation. The underlying mechanisms may involve delayed myelination or demyelination of nerves; alteration in the S-adenosylmethionine:S-adenosylhomocysteine ratio; imbalance of neurotrophic and neurotoxic cytokines; and/or accumulation of lactate in brain cells. This review summarizes the current knowledge concerning infantile vitamin B(12) deficiency, including a pooled analysis of case studies of infants born to mothers with untreated pernicious anemia or a strict vegetarian lifestyle and a discussion of the mechanisms that may underlie the manifestations of deficiency.

Omega-3 fatty acids in ADHD and related neurodevelopmental disorders.

Omega-3 fatty acids are dietary essentials, and are critical to brain development and function. Increasing evidence suggests that a relative lack of omega-3 may contribute to many psychiatric and neurodevelopmental disorders. This review focuses on the possible role of omega-3 in attention-deficit/hyperactivity disorder (ADHD) and related childhood developmental disorders, evaluating the existing evidence from both research and clinical perspectives. Theory and experimental evidence support a role for omega-3 in ADHD, dyslexia, developmental coordination disorder (DCD) and autism. Results from controlled treatment trials are mixed, but the few studies in this area have involved different populations and treatment formulations. Dietary supplementation with fish oils (providing EPA and DHA) appears to alleviate ADHD-related symptoms in at least some children, and one study of DCD children also found benefits for academic achievement. Larger trials are now needed to confirm these findings, and to establish the specificity and durability of any treatment effects as well as optimal formulations and dosages. Omega-3 is not supported by current evidence as a primary treatment for ADHD or related conditions, but further research in this area is clearly warranted. Given their relative safety and general health benefits, omega-3 fatty acids offer a promising complementary approach to standard treatments.

Are cross-species measures of sensorimotor gating useful for the discovery of procognitive cotreatments for schizophrenia?

Prepulse inhibition of startle (PPI), a measure of sensorimotor gating used to identify antipsychotics, is reduced in schizophrenia patients and in rodents treated with dopamine agonists or glutamate antagonists. The National Institute of Mental Health (NIMH)-funded Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) program has initiated a new era in the development of procognitive cotreatments in schizophrenia, independently of treating positive symptoms. Although PPI is not a cognitive process per se, such abnormalities in attention may be predictive of or lead to cognitive deficits. Since first-generation antipsychotics block PPI deficits induced by dopamine agonists, this model cannot identify cognitive enhancers for use as cotreatments with antipsychotics. PPI deficits caused by glutamate antagonists, like the exacerbation of symptoms they produce in patients, are insensitive to dopamine antagonists, but reduced by clozapine. Similarly, both PPI and cognitive deficits in schizophrenia patients are insensitive to first-generation antipsychotics, but attenuated by clozapine. Hence, treatment-induced reversals of glutamate antagonist effects on PPI may provide animal and human models to identify treatments of cognitive deficits in patients already treated with existing antipsychotics.

[Three cases with severe motor and intellectual disabilities presenting the severest condition caused by prolonged non-convulsive status epilepticus].

Three patients with severe motor and intellectual disabilities presented deterioration of the activities of daily living, which was revealed to be caused by prolonged non-convulsive status epilepticus (NCSE). Their condition improved by the treatment with antiepileptics. Case 1, a 4-year-old girl with profound psychomotor retardation and past history of West syndrome of unknown etiology, became unable to sit and eat orally above age of two years. EEG showed continuous generalized slow spike and wave bursts indicating NCSE. Continuous intravenous infusion of midazolam abolished EEG abnormalities of NCSE, and she regained the ability of oral feeding. Case 2, a 3-year-old boy with Angelman syndrome and past history of West syndrome, presented decreased mental response, poor oral intake and somnolence. EEG showed continuous slow spike and wave bursts, indicating NCSE. High-dose phenobarbital therapy and continuous intravenous injection of vitamin B6 were effective, and remarkably improved his psychomotor activities. Case 3, a 3-year-old boy with Lennox-Gastaut syndrome, developed decreased psychomotor activity and loss of vocalization and walking. He could not sit by himself and became nearly bed-ridden. EEG showed very frequent generalized spike and wave bursts, showing NCSE. Continuous infusion of thiopental diminished NCSE, and he could walk again. Psychomotor deterioration in patients with severe motor and intellectual disabilities may be caused by NCSE, which should not be overlooked.

Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution.

INTRODUCTION: Normal brain development and function depend on the active transport of folates across the blood-brain barrier. The folate receptor-1 (FR 1) protein is localized at the basolateral surface of the choroid plexus, which is characterized by a high binding affinity for circulating 5-methyltetrahydrofolate (5-MTHF). PATIENTS AND METHODS: We report on the clinical and metabolic findings among five children with normal neurodevelopmental progress during the first four to six months followed by the acquisition of a neurological condition which includes marked irritability, decelerating head growth, psychomotor retardation, cerebellar ataxia, dyskinesias (choreoathetosis, ballism), pyramidal signs in the lower limbs and occasional seizures. After the age of six years the two oldest patients also manifested a central visual disorder. Known disorders have been ruled out by extensive investigations. Cerebrospinal fluid (CSF) analysis included determination of biogenic monoamines, pterins and 5-MTHF. RESULTS: Despite normal folate levels in serum and red blood cells with normal homocysteine, analysis of CSF revealed a decline towards very low values for 5-methyltetrahydrofolate (5-MTHF), which suggested disturbed transport of folates across the blood-brain barrier. Genetic analysis of the FR 1 gene revealed normal coding sequences. Oral treatment with doses of the stable compound folinic acid (0.5-1 mg/kg/day Leucovorin(R)) resulted in clinical amelioration and normalization of 5-MTHF values in CSF. CONCLUSION: Our findings identified a new condition manifesting after the age of 6 months which was accompanied by low 5-MTHF in cerebrospinal fluid and responded to oral supplements with folinic acid. However, the cause of disturbed folate transfer across the blood-brain barrier remains unknown.

Effects of anti-Parkinsonian drugs on neurobehavioural changes induced by bilateral 6-hydroxydopamine lesions in rats.

1. Effects of anti-Parkinsonian drugs on neurobehavioural changes induced by bilateral lesions of dopaminergic neurons were investigated in rats. 2. Dopaminergic neurons in rats were lesioned bilaterally by injection of 6-hydroxydopamine (6-OHDA; 8 micrograms) into the medial forebrain bundle at the level of the posterolateral hypothalamus. As a result, a decrease in locomotor activity and marked catalepsy and prolongation of grasping time were observed. 3. Levodopa, talipexole, bromocriptine and theophylline dose-dependently antagonized the decrease in locomotor activity induced by bilateral 6-OHDA lesions. These drugs also showed antagonistic effects on the appearance of catalepsy and prolongation of grasping time induced by bilateral 6-OHDA lesions. In contrast, trihexyphenidyl showed no antagonizing effect on the neurobehavioural changes induced by 6-OHDA lesions at any concentration tested. 4. Combined treatment with levodopa and talipexole antagonized the neurobehavioural changes induced by bilateral 6-OHDA lesions, whereas no marked changes were observed when either drug was administered separately. The same findings were noted with the simultaneous use of either levodopa (2 mg/kg) and theophylline (2 mg/kg) or talipexole (0.005 mg/kg) and theophylline (2 mg/kg). 5. These results indicate that this model may be useful for estimating the effects of drugs in the treatment of Parkinson's disease.

[The use of melipramine in treating patients with a depressive syndrome accompanied by motor retardation]. / Primenenie melipamina v lechenii bol'nykh s depressivnym sindromom, soprovozhdaiushchimsia dvigatel'noi zatormozhennost'iu.

A study of 49 patients with the depressive syndrome and showing different motor activity indicates that melipramin treatment proved more effective during the first week of treatment. The obtained data are confirmed by results of experiments with immobilized animals.