This review describes therapeutically relevant mechanisms of action of botulinum toxin (BT). BT's molecular mode of action includes extracellular binding to glycoproteine structures on cholinergic nerve terminals and intracellular blockade of the acetylcholine secretion. BT affects the spinal stretch reflex by blockade of intrafusal muscle fibres with consecutive reduction of Ia/II afferent signals and muscle tone without affecting muscle strength (reflex inhibition). This mechanism allows for antidystonic effects not only caused by target muscle paresis. BT also blocks efferent autonomic fibres to smooth muscles and to exocrine glands. Direct central nervous system effects are not observed, since BT does not cross the blood-brain-barrier and since it is inactivated during its retrograde axonal transport. Indirect central nervous system effects include reflex inhibition, normalisation of reciprocal inhibition, intracortical inhibition and somatosensory evoked potentials. Reduction of formalin-induced pain suggests direct analgesic BT effects possibly mediated through blockade of substance P, glutamate and calcitonin gene related peptide. (+info)
Acute effects of selective serotonin reuptake inhibitors on neuroleptic-induced catalepsy in mice.
(26/98)
Depression found in Parkinson disease (PD) usually responds to selective serotonin reuptake inhibitors (SSRIs). Drugs that modify experimental neuroleptic catalepsy (NC) might affect extrapyramidal symptoms in PD. Therefore, the effects of SSRIs on NC were tested in mice, 26-36 g, separated by sex. Catalepsy was induced with haloperidol (H; 1 mg/kg, ip) and measured at 30-min intervals using a bar test. An SSRI (sertraline, ST; paroxetine, PX; fluoxetine) or vehicle (C) was injected ip 30 min before H. Dunnett's test was used for comparison of means. ST (1-5 mg/kg) or PX (1-5 mg/kg) attenuated NC, with a similar inhibition found in both sexes (5 mg/kg, 180 min: ST - males: 124 +/- 10 vs 714 +/- 15 s in C; females: 116 +/- 10 vs 718 +/- 6 s in C; PX - males: 106 +/- 10 vs 714 +/- 14 s in C; females: 102 +/- 10 vs 715 +/- 14 s in C). At 0.3 mg/kg, neither of these drugs affected NC. Fluoxetine (1-25 mg/kg) also inhibited catalepsy, although the effect was not dose-dependent; no differences were observed between males and females (5 mg/kg, 180 min: males, 185 +/- 14 vs 712 +/- 14 s in C; females, 169 +/- 10 vs 710 +/- 19 s in C). For these SSRIs, maximal inhibition of NC was obtained with 5 mg/kg, 180 min after H. These results are consistent with the hypothesis that serotonergic mechanisms modulate nigrostriatal transmission, and suggest that SSRIs are possibly safe in depressive PD patients. (+info)
Headache and botulinum toxin.
(27/98)
The authors discuss clinical and international experience about botulinum toxins (BTX types A and B) in headache treatment. Data from literature suggest good results for the treatment of tension-type headache, migraine and chronic tension-type headache. In the present paper mechanisms of action and injection sites will also be discussed. (+info)
Fyn is required for haloperidol-induced catalepsy in mice.
(28/98)
Fyn-mediated tyrosine phosphorylation of N-methyl-D-aspartate (NMDA) receptor subunits has been implicated in various brain functions, including ethanol tolerance, learning, and seizure susceptibility. In this study, we explored the role of Fyn in haloperidol-induced catalepsy, an animal model of the extrapyramidal side effects of antipsychotics. Haloperidol induced catalepsy and muscle rigidity in the control mice, but these responses were significantly reduced in Fyn-deficient mice. Expression of the striatal dopamine D(2) receptor, the main site of haloperidol action, did not differ between the two genotypes. Fyn activation and enhanced tyrosine phosphorylation of the NMDA receptor NR2B subunit, as measured by Western blotting, were induced after haloperidol injection of the control mice, but both responses were significantly reduced in Fyn-deficient mice. Dopamine D(2) receptor blockade was shown to increase both NR2B phosphorylation and the NMDA-induced calcium responses in control cultured striatal neurons but not in Fyn-deficient neurons. Based on these findings, we proposed a new molecular mechanism underlying haloperidol-induced catalepsy, in which the dopamine D(2) receptor antagonist induces striatal Fyn activation and the subsequent tyrosine phosphorylation of NR2B alters striatal neuronal activity, thereby inducing the behavioral changes that are manifested as a cataleptic response. (+info)
Modulation of Kv2.1 channel gating and TEA sensitivity by distinct domains of SNAP-25.
(29/98)
Distinct domains within the SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) proteins, STX1A (syntaxin 1A) and SNAP-25 (synaptosome-associated protein-25 kDa), regulate hormone secretion by their actions on the cell's exocytotic machinery, as well as voltage-gated Ca2+ and K+ channels. We examined the action of distinct domains within SNAP-25 on Kv2.1 (voltage gated K+ 2.1) channel gating. Dialysis of N-terminal SNAP-25 domains, S197 (SNAP-25(1-197)) and S180 (SNAP-25(1-180)), but not S206 (full-length SNAP-25(1-206)) increased the rate of Kv2.1 channel activation and slowed channel inactivation. Remarkably, these N-terminal SNAP-25 domains, acting on the Kv2.1 cytoplasmic N-terminus, potentiated the external TEA (tetraethylammonium)-mediated block of Kv2.1. To further examine whether these are effects of the channel pore domain, internal K+ was replaced with Na+ and external K+ was decreased from 4 to 1 mM, which decreased the IC50 of the TEA block from 6.8+/-0.9 mM to >100 mM. Under these conditions S180 completely restored TEA sensitivity (7.9+/-1.5 mM). SNAP-25 C-terminal domains, SNAP-25(198-206) and SNAP-25(181-197), had no effect on Kv2.1 gating kinetics. We conclude that different domains within SNAP-25 can form distinct complexes with Kv2.1 to execute a fine allosteric regulation of channel gating and the architecture of the outer pore structure in order to modulate cell excitability. (+info)
Nonsurgical treatment of chronic anal fissure: nitroglycerin and dilatation versus nifedipine and botulinum toxin.
(30/98)
BACKGROUND: Surgical sphincterotomy for chronic anal fissure can cause fecal incontinence. This has led to the investigation of nonsurgical treatment options that avoid permanent damage to the internal anal sphincter. METHODS: We conducted a retrospective, ongoing chart review with telephone follow-up of 88 patients treated for chronic anal fissure between November 1996 and December 2002. During the first half of the study period, patients were treated with topical nitroglycerin and pneumatic dilatation. With the availability of new therapies in June 1999, subsequent patients received topical nifedipine and botulinum toxin injections (30-100 units). Lateral anal sphincterotomy was reserved for patients who failed medical treatment. RESULTS: In 98% of patients the fissure healed with conservative nonsurgical treatment. The combination of nifedipine and botulinum toxin was superior to nitroglycerin and pneumatic dilatation with respect to both healing (94% v. 71%, p < 0.05) and recurrence rate (2% v. 27%, p < 0.01). There was no statistical difference between the number of dilatations and botulinum toxin injections needed to achieve healing. Three patients who received botulinum toxin reported mild transient flatus incontinence. At an average telephone follow-up of 27 months, 92% of patients reported having no pain or only mild occasional pain with bowel movements. CONCLUSIONS: Chronic anal fissures can be simply and effectively treated medically without the risk of incontinence associated with sphincterotomy. Topical nifedipine and botulinum toxin injections are an excellent combination, associated with a low recurrence rate and minimal side effects. (+info)
Therapeutic interventions for tone abnormalities in cerebral palsy.
(31/98)
Cerebral palsy (CP) is a common cause of movement disorders in children. The upper motor neuron syndrome of CP leads to several types of muscle overactivity, including spasticity. Reduction of muscle overactivity may be an important treatment goal, to improve comfort, care, and active function and to prevent future musculoskeletal complications. After a comprehensive team evaluation, a treatment plan is generated. Treatments may include physical and occupational therapy, oral medications, botulinum toxin and/or phenol injections, intrathecal baclofen, selective dorsal rhizotomy, and orthopedic surgery. Successful and early prevention of contracture may reduce the need for later corrective surgery. (+info)
Essential tremor-the most common movement disorder in older people.
(32/98)
Essential tremor (ET) affects approximately 4% of the population above 65 years of age. The traditional view that ET is a familial monosymptomatic disorder with a benign prognosis has recently been challenged, as it is now known to be a progressive and clinically heterogeneous condition with sporadic and familial forms. The pathogenesis of ET is not fully understood, though a disordered central mechanism is the most likely site of origin with possible modulation by muscle adrenoreceptors. The limited post-mortem studies have not shown consistent abnormalities in the brains of ET patients. ET is often misdiagnosed as Parkinson's disease, particularly in the older population. Tremor amplitude increases with age, accounting for substantial disability in older people. Current therapy (drugs and neurosurgery) has significant limitations in older people. A better understanding of its pathophysiology in the future will help in developing more effective therapy, including neuroprotective strategies. (+info)