Beneficial effects of metformin on haloperidol-induced motor deficits in rats. A behavioral assessment

Abstract Objective: One of the most common side effects of haloperidol is the extrapyramidal syndrome, resulting from inhibition of nigrostriatal dopaminergic circuits and mitochondrial dysfunction due to structural similarities to pyridinium derivative, MPP+ that induce oxidative stress. In exchange, the use of metformin appears to enhance neurogenesis, energy metabolism, and oxidative status, so these properties can be speculated in the context of drug-induced pseudoparkinsonism by haloperidol. Methods: To assess motor coordination and activity, rodents were divided into four groups: CTR (n = 10) - animals that received distilled water, METF (n = 10) - animals that received metformin 500 mg / kgbw, HAL (n = 10) - animals that received haloperidol 2mg / kgbw, HALMETF (n = 10) - haloperidol 2mg / kgbw and metformin 500 mg / kgbw. The treatment was administered for 34 days at the same time by gastric gavage, during which time behavioral tests, rotarod (days 7, 14, 21, 28), catalepsy (day 30), open field (day 32) and novel object recognition (day 34) were performed. Results: The monitored parameters, showed significant differences between the groups of interest (HAL and HALMETF respectively), so that the administration of metformin at the beginning of treatment reduces the cataleptic behavior. The HALMETF group shows an attenuation of the motor deficit during the rotarod test and the freezing period from the Open Field test, is diminished. Conclusions: Metformin treatment has a beneficial effect in haloperidol-treated rats, demonstrated by decreased cataleptic behavior, improved motor performance and reduced haloperidol-induced anxiety behavior.

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Fluoxetine rescues rotarod motor deficits in Mecp2 heterozygous mouse model of Rett syndrome via brain serotonin

10.1101/2020.06.12.147876 ◽

2020 ◽

Author(s):

Claudia Villani ◽

Giuseppina Sacchetti ◽

Mirjana Carli ◽

Roberto W. Invernizzi

Keyword(s):

Rett Syndrome ◽

Motor Skill ◽

Motor Coordination ◽

Protein A ◽

Specific Area ◽

Repeated Administration ◽

Skill Learning ◽

Motor Deficits ◽

Loss Of Function ◽

Beneficial Effects

AbstractMotor skill is a specific area of disability of Rett syndrome (RTT), a rare disorder occurring almost exclusively in girls, caused by loss-of-function mutations of the X-linked methyl-CpG-binding protein2 (MECP2) gene, encoding the MECP2 protein, a member of the methyl-CpG-binding domain nuclear proteins family. Brain 5-HT, which is defective in RTT patients and Mecp2 mutant mice, regulates motor circuits and SSRIs enhance motor skill learning and plasticity.In the present study, we used heterozygous (Het) Mecp2 female and Mecp2-null male mice to investigate whether fluoxetine, a SSRI with pleiotropic effects on neuronal circuits, rescues motor coordination deficits. Repeated administration of 10 mg/kg fluoxetine fully rescued rotarod deficit in Mecp2 Het mice regardless of age, route of administration or pre-training to rotarod. The motor improvement was confirmed in the beam walking test while no effect was observed in the hanging-wire test, suggesting a preferential action of fluoxetine on motor coordination. Citalopram mimicked the effects of fluoxetine, while the inhibition of 5-HT synthesis abolished the fluoxetine-induced improvement of motor coordination. Mecp2 null mice, which responded poorly to fluoxetine in the rotarod, showed reduced 5-HT synthesis in the prefrontal cortex, hippocampus and striatum, and reduced efficacy of fluoxetine in raising extracellular 5-HT as compared to female mutants. No sex differences were observed in the ability of fluoxetine to desensitize 5-HT1A autoreceptors upon repeated administration. These findings indicate that fluoxetine rescues motor coordination in Mecp2 Het mice through its ability to enhance brain 5-HT and suggest that drugs enhancing 5-HT neurotransmission may have beneficial effects on motor symptoms of RTT.

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The importance of visuo-motor coordination in upper limb rehabilitation after ischemic stroke by robotic therapy

Balneo Research Journal ◽

10.12680/balneo.2019.244 ◽

2019 ◽

Vol 10 (10.2) ◽

pp. 82-89 ◽

Cited By ~ 1

Author(s):

Angelo Bulboaca ◽

Ioana Stanescu ◽

Gabriela Dogaru ◽

Paul-Mihai Boarescu ◽

Adriana Elena Bulboaca

Keyword(s):

Upper Limb ◽

Lower Limb ◽

Motor Coordination ◽

Functional Integration ◽

Oculomotor System ◽

Modern Method ◽

Motor Deficit ◽

Motor Deficits ◽

Upper Limb Rehabilitation ◽

Hand Coordination

Abstract Stroke is an acute hypoperfusion of cerebral parenchyma that most often leads to outstanding motor deficits that can last for the rest of the patient’s life. The purpose of the neurorehabilitation process is to limit, as far is possible for the motor deficits and to bring the patient to an independent life. A modern method consists in robotic neurorehabilitation which is more and more used, associated with functional electrical stimulation (FES). At the lower limb, the use of robotic rehabilitation associated with FES is already considered a success due to relatively stereotypical movements of the lower limb. In opposition, the upper limb is more difficult to rehabilitate due to its more complex movements. Therefore, eye-hand coordination (EHC) constitutes an important factor that is conditioning the rehabilitation progress. The eye-hand coordination can be brutally disturbed by stroke with critical consequences on motor-executive component. The EHC development depends on the interaction between a feedback complex and the prediction of the upper limb motility in the space, and requires the association between visual system, oculomotor system and hand motor system. We analyzed the stroke impact on this sensorial-motor functional integration and looked for a possible solution for the interruption of coordination between eyes and the movements of the superior limb. We consider that our study can contribute to a better understanding and to a faster rehabilitation of the motor deficit in the upper limb after stroke. Key words: stroke, rehabilitation, eye-hand coordination, robotic neurorehabilitation,

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Long-term motor deficit in brain tumour surgery with preserved intra-operative motor-evoked potentials

Brain Communications ◽

10.1093/braincomms/fcaa226 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Davide Giampiccolo ◽

Cristiano Parisi ◽

Pietro Meneghelli ◽

Vincenzo Tramontano ◽

Federica Basaldella ◽

...

Keyword(s):

Evoked Potentials ◽

Brain Tumour ◽

Evoked Potential ◽

Corticospinal Tract ◽

Motor Evoked Potentials ◽

Motor Evoked Potential ◽

Motor Deficit ◽

Motor Deficits ◽

Brain Tumour Surgery

Abstract Muscle motor-evoked potentials are commonly monitored during brain tumour surgery in motor areas, as these are assumed to reflect the integrity of descending motor pathways, including the corticospinal tract. However, while the loss of muscle motor-evoked potentials at the end of surgery is associated with long-term motor deficits (muscle motor-evoked potential-related deficits), there is increasing evidence that motor deficit can occur despite no change in muscle motor-evoked potentials (muscle motor-evoked potential-unrelated deficits), particularly after surgery of non-primary regions involved in motor control. In this study, we aimed to investigate the incidence of muscle motor-evoked potential-unrelated deficits and to identify the associated brain regions. We retrospectively reviewed 125 consecutive patients who underwent surgery for peri-Rolandic lesions using intra-operative neurophysiological monitoring. Intraoperative changes in muscle motor-evoked potentials were correlated with motor outcome, assessed by the Medical Research Council scale. We performed voxel–lesion–symptom mapping to identify which resected regions were associated with short- and long-term muscle motor-evoked potential-associated motor deficits. Muscle motor-evoked potentials reductions significantly predicted long-term motor deficits. However, in more than half of the patients who experienced long-term deficits (12/22 patients), no muscle motor-evoked potential reduction was reported during surgery. Lesion analysis showed that muscle motor-evoked potential-related long-term motor deficits were associated with direct or ischaemic damage to the corticospinal tract, whereas muscle motor-evoked potential-unrelated deficits occurred when supplementary motor areas were resected in conjunction with dorsal premotor regions and the anterior cingulate. Our results indicate that long-term motor deficits unrelated to the corticospinal tract can occur more often than currently reported. As these deficits cannot be predicted by muscle motor-evoked potentials, a combination of awake and/or novel asleep techniques other than muscle motor-evoked potentials monitoring should be implemented.

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Neurophysiologic Mapping of Thalamocortical Tract in Asleep Craniotomies: Promising Results From an Early Experience

Operative Neurosurgery ◽

10.1093/ons/opaa330 ◽

2020 ◽

Author(s):

Mirela V Simon ◽

Daniel K Lee ◽

Bryan D Choi ◽

Pratik A Talati ◽

Jimmy C Yang ◽

...

Keyword(s):

General Anesthesia ◽

Corticospinal Tract ◽

Sensory Function ◽

Motor Deficit ◽

Motor Deficits ◽

Central Sulcus ◽

Postcentral Gyrus ◽

Subcortical Stimulation ◽

Subcortical Mapping

Abstract BACKGROUND Subcortical mapping of the corticospinal tract has been extensively used during craniotomies under general anesthesia to achieve maximal resection while avoiding postoperative motor deficits. To our knowledge, similar methods to map the thalamocortical tract (TCT) have not yet been developed. OBJECTIVE To describe a neurophysiologic technique for TCT identification in 2 patients who underwent resection of frontoparietal lesions. METHODS The central sulcus (CS) was identified using the somatosensory evoked potentials (SSEP) phase reversal technique. Furthermore, monitoring of the cortical postcentral N20 and precentral P22 potentials was performed during resection. Subcortical electrical stimulation in the resection cavity was done using the multipulse train (case #1) and Penfield (case #2) techniques. RESULTS Subcortical stimulation within the postcentral gyrus (case #1) and in depth of the CS (case #2), resulted in a sudden drop in amplitudes in N20 (case #1) and P22 (case #2), respectively. In both patients, the potentials promptly recovered once the stimulation was stopped. These results led to redirection of the surgical plane with avoidance of damage of thalamocortical input to the primary somatosensory (case #1) and motor regions (case #2). At the end of the resection, there were no significant changes in the median SSEP. Both patients had no new long-term postoperative sensory or motor deficit. CONCLUSION This method allows identification of TCT in craniotomies under general anesthesia. Such input is essential not only for preservation of sensory function but also for feedback modulation of motor activity.

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Severe hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with fluoxetine: case report

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2006000100031 ◽

2006 ◽

Vol 64 (1) ◽

pp. 142-145 ◽

Cited By ~ 9

Author(s):

Carlos Alexandre Twardowschy ◽

Cristina Buselatto Bertolucci ◽

Cleverson de Macedo Gracia ◽

Marta Ângela de Souza Brandão

Keyword(s):

Emergency Service ◽

Patient Experiences ◽

Motor Deficits ◽

Muscle Rigidity ◽

Severe Hyponatremia ◽

Drug Induced ◽

Urinary Osmolality ◽

X Ray ◽

Inappropriate Secretion ◽

Chest X Ray

Hyponatremia is a significant complication of treatment with serotonin selective reuptake inhibitors (SSRI). We describe a case of a 53-year-old woman that was started on fluoxetine 20 mg/day for depression. Nine days later, the patient started with weakness, nausea, progressing to confusion, inapetence and vomit. Three hours later she became unresponsive and had a generalized seizure. She was brought to our emergency service. On admission, the patient was normovolemic, without focal motor deficits, but had mild generalized muscle rigidity and Babinski's sign bilaterally. Serum sodium was 105 mmol/L, serum osmolality, 220 mmol/L, and urinary osmolality, 400 mmol/L. The other laboratory exams, chest X-ray, cerebrospinal fluid and cranium tomography were normal. She was found to have fluoxetine-induced SIADH and it was descontinued. We started the hyponatremia correction and, in 5 days, the mental status of the patient gradually returned to a normal baseline, paralleling the resolution of her hyponatremia, without recurrence. Hyponatremia and SIADH should be considered if a patient experiences deterioration in his or her clinical condition while taking SSRI. The use of SSRI antidepressants should be remembered in the differential diagnosis of drug-induced hyponatremia.

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Visuo-motor integration, vision perception and attention in mTBI patients. Preliminary findings

PLoS ONE ◽

10.1371/journal.pone.0250598 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0250598

Author(s):

Mariagrazia Benassi ◽

Davide Frattini ◽

Sara Garofalo ◽

Roberto Bolzani ◽

Tony Pansell

Keyword(s):

Spatial Attention ◽

Motor Skills ◽

Motor Coordination ◽

Fine Motor ◽

Motor Deficits ◽

Motor Ability ◽

Critical Flicker Fusion ◽

Visuomotor Coordination ◽

Form Recognition ◽

Flicker Fusion

Patients with mild traumatic brain injuries (mTBI) often report difficulties in motor coordination and visuo-spatial attention. However, the consequences of mTBI on fine motor and visuo-motor coordination are still not well understood. We aimed to evaluate whether mTBI had a concomitant effect on fine motor ability and visuo-motor integration and whether this is related to visual perception and visuo-spatial attention impairments, including patients at different symptoms stage. Eleven mTBI patients (mean age 22.8 years) and ten healthy controls participated in the study. Visuo-motor integration of fine motor abilities and form recognition were measured with the Beery-Buktenica Developmental Test of Visual-Motor Integration test, motion perception was evaluated with motion coherence test, critical flicker fusion was measured with Pocket CFF tester. Visuo-spatial was assessed with the Ruff 2 & 7 Selection Attention Test. mTBI patients showed reduced visuo-motor integration, form recognition, and motor deficits as well as visuo-spatial attention impairment, while motion perception and critical flicker fusion were not impaired. These preliminary findings suggest that the temporary brain insults deriving from mTBI compromise fine motor skills, visuomotor integration, form recognition, and visuo-spatial attention. The impairment in visuo-motor coordination was associated with speed in visuo-attention and correlated with symptoms severity while motor ability was correlated with time since concussion. Given the strong correlation between visuomotor coordination and symptom severity, further investigation with a larger sample seems warranted. Since there appeared to be differences in motor skills with respect to symptom stage, further research is needed to investigate symptom profiles associated with visuomotor coordination and fine motor deficits in mTBI patients.

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Daily Subacute Paraquat Exposure Decreases Muscle Function and Substantia Nigra Dopamine Level

Physiological Research ◽

10.33549/physiolres.932386 ◽

2013 ◽

pp. 313-321 ◽

Cited By ~ 3

Author(s):

M. A. FAHIM ◽

S. SHEHAB ◽

A. NEMMAR ◽

A. ADEM ◽

S. DHANASEKARAN ◽

...

Keyword(s):

Tyrosine Hydroxylase ◽

Substantia Nigra ◽

High Performance ◽

Motor Coordination ◽

Neuronal Loss ◽

Male Rats ◽

Substantia Nigra Pars Compacta ◽

Motor Deficit ◽

Dopamine Level ◽

Dopaminergic Neurodegeneration

The use of the herbicide paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride; PQ) which is widely used in agriculture is known to cause dopaminergic neurotoxicity. However, the mechanisms underlying this effect are not fully understood. This present study investigated the behavioral manifestations, motor coordination, and dopaminergic neurodegeneration following exposure to PQ. Male rats were injected with PQ (10 mg/kg i.p.) daily for three weeks. Rotarod systems were used for measuring locomotor activity and motor coordination. The effects of PQ on dorsiflexor, electrophysiologically-induced muscle contraction were studied. Dopamine concentrations in the ventral mesencephalon were measured by high performance liquid chromatography and the number of dopaminergic neurons in substantia nigra pars compacta was estimated by tyrosine hydroxylase immunohistochemistry. PQ induced difficulty in movement and significant reduction in motor activity and twitch tension at the dorsiflexor skeletal muscle. The number of tyrosine hydroxylase positive neurons was significantly less in the substantia nigra pars compacta and nigral dopamine level was significantly reduced in PQ treated animals (20.4±3.4 pg/mg) when compared with control animals (55.0±2.4 pg/mg wet tissue). Daily treatment of PQ for three weeks induces selective dopaminergic neuronal loss in the substantia nigra and significant behavioral and peripheral motor deficit effects.

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Impact of pharmacological agents on mitochondrial function: a growing opportunity?

Biochemical Society Transactions ◽

10.1042/bst20190280 ◽

2019 ◽

Vol 47 (6) ◽

pp. 1757-1772 ◽

Cited By ~ 3

Author(s):

Megan L. Stoker ◽

Emma Newport ◽

James C. Hulit ◽

A. Phillip West ◽

Karl J. Morten

Keyword(s):

Side Effects ◽

Mitochondrial Function ◽

Immune Modulation ◽

Antiviral Agents ◽

Aging Population ◽

Drug Induced ◽

Pharmacological Agents ◽

Beneficial Effects ◽

Drug Classes ◽

Target Effects

Present-day drug therapies provide clear beneficial effects as many diseases can be driven into remission and the symptoms of others can be efficiently managed; however, the success of many drugs is limited due to both patient non-compliance and adverse off-target or toxicity-induced effects. There is emerging evidence that many of these side effects are caused by drug-induced impairment of mitochondrial function and eventual mitochondrial dysfunction. It is imperative to understand how and why drug-induced side effects occur and how mitochondrial function is affected. In an aging population, age-associated drug toxicity is another key area of focus as the majority of patients on medication are older. Therefore, with an aging population possessing subtle or even more dramatic individual differences in mitochondrial function, there is a growing necessity to identify and understand early on potentially significant drug-associated off-target effects and toxicity issues. This will not only reduce the number of unwanted side effects linked to mitochondrial toxicity but also identify useful mitochondrial-modulating agents. Mechanistically, many successful drug classes including diabetic treatments, antibiotics, chemotherapies and antiviral agents have been linked to mitochondrial targeted effects. This is a growing area, with research to repurpose current medications affecting mitochondrial function being assessed in cancer, the immune system and neurodegenerative disorders including Parkinson's disease. Here, we review the effects that pharmacological agents have on mitochondrial function and explore the opportunities from these effects as potential disease treatments. Our focus will be on cancer treatment and immune modulation.

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Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia

eLife ◽

10.7554/elife.68039 ◽

2021 ◽

Vol 10 ◽

Author(s):

Jenny I Aguilar ◽

Mary Hongying Cheng ◽

Josep Font ◽

Alexandra C Schwartz ◽

Kaitlyn Ledwitch ◽

...

Keyword(s):

High Speed ◽

Molecular Mechanisms ◽

Motor Coordination ◽

Neurodegenerative Disorder ◽

Expression System ◽

Distinct Type ◽

Underlying Disease ◽

Deficiency Syndrome ◽

Motor Deficits ◽

Therapeutic Implications

Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution. We show that hDAT R445C Drosophila exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination with chloroquine, a lysosomal inhibitor that enhanced DAT expression in a heterologous expression system. Together, these studies shed some light on how a DTDS-linked DAT mutation underlies DA dysfunction and, possibly, clinical phenotypes shared by DTDS and PD.

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Drug-Induced Vanishing Bile Duct Syndrome: From Pathogenesis to Diagnosis and Therapeutics

Seminars in Liver Disease ◽

10.1055/s-0041-1729972 ◽

2021 ◽

Author(s):

Fernando Bessone ◽

Nidia Hernández ◽

Mario Tanno ◽

Marcelo G. Roma

Keyword(s):

Bile Duct ◽

Diagnostic Tools ◽

Drug Induced ◽

Vanishing Bile Duct Syndrome ◽

Beneficial Effects ◽

Intrahepatic Bile Ducts ◽

Chronic Cholestasis ◽

Vanishing Bile Duct ◽

Therapeutic Alternatives ◽

Duct Syndrome

AbstractThe most concerned issue in the context of drug/herb-induced chronic cholestasis is vanishing bile duct syndrome. The progressive destruction of intrahepatic bile ducts leading to ductopenia is usually not dose dependent, and has a delayed onset that should be suspected when abnormal serum cholestasis enzyme levels persist despite drug withdrawal. Immune-mediated cholangiocyte injury, direct cholangiocyte damage by drugs or their metabolites once in bile, and sustained exposure to toxic bile salts when biliary epithelium protective defenses are impaired are the main mechanisms of cholangiolar damage. Current therapeutic alternatives are scarce and have not shown consistent beneficial effects so far. This review will summarize the current literature on the main diagnostic tools of ductopenia and its histological features, and the differential diagnostic with other ductopenic diseases. In addition, pathomechanisms will be addressed, as well as the connection between them and the supportive and curative strategies for ductopenia management.

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