Dose‐ and volume dependent‐response to intramuscular injection of botulinum neurotoxin‐A optimizes muscle force decrement in mice

Abstract

Botulinum neurotoxin-A (BoNTA) is a potent neurotoxin used to alter muscle tone to manage spasticity and to provide tendon bioprotection; however, the appropriate dose and injection volume to administer is not defined. Male mice (n ¼ 120) received BoNTA injections into one gastrocnemius with either a constant volume (10 ml) with a variable dose (1, 3, 6 U/kg) or a constant dose (3 U/kg) in a variable volume (2.5, 5, 10, 20, 30 ml). Electromyographic (EMG) examination, muscle force generation (MFG), and wet muscle mass were measured in the ipsilateral and contralateral limbs at 1, 2, 4, or 12 weeks post-injection. MFG and EMG responses decreased to approximately 40% of contralateral after a 1 U/kg injection and 0% of contralateral by 3 and 6 U/kg injection at 1 week after injection. Neuromuscular blockade was greatest with a 10 ml injection volume. MFG, EMG examination, and wet muscle mass reached contralateral values 12 weeks after injection for all injection doses and volumes tested. Effective injection doses and volumes were identified for producing full and partial neuromuscular blockade in the mouse gastrocnemius. These findings have important clinical implications in the intramuscular administration of BoNTA to manage muscle tone. ß

Assessing the immediate impact of botulinum toxin injection on impedance of spastic muscle

“…This made it impractical to use regression analysis for evaluation of whether changes of resistance were associated with the injection dose. In a previous electromyography (EMG) study, force generation and mass in the injected muscle confirmed effects of dose and injection volume on neuromuscular blockade in the mouse gastrocnemius [29]. By tracking changes of compound muscle action potentials (CMAPs), researchers found a detectable ‘blocking’ effect took place 24–48 hours after the BoNT-A injection followed by a progressive decrease of CMAP amplitude with peak reduction around 6–7 days and a slow recovery process in 30 days [3].…”

The Effect of Botulinum Neurotoxin-A on Blood Flow in Rats: A Potential Mechanism for Treatment of Raynaud Phenomenon

“…6 The BoNTA increased blood flow in a rabbit model for 8 weeks, and BoNTA effects are evident for 3-6 months in rats and mice depending on the dose and volume injected. 11,[17][18] Based on the proposed mechanism of action, BoNTA should have similar effects on vasodilation through sympathetic inhibition as it does on the nerve terminals at the neuromuscular junction. In humans, BoNTA could be expected to be effective for at least 3-6 months.…”

“…[1][2][3][4][5][6] In addition, botulinum toxin is emerging as a treatment modality for Raynaud phenomenon. [7][8][9][10] The mechanism of action of BoNTA at the neuromuscular junction and the functional recovery of the nerve and muscle are well established [11][12][13][14][15][16][17][18] ; however, little information is available regarding toxin effects on the local vasculature. [7][8][9]19 Arteriolar diameter and blood flow is predominantly controlled by the sympathetic nervous system, which releases norepinephrine after stimulation and results in ␣-adrenergic receptor-mediated vasoconstriction.…”

Botulinum Neurotoxin A Injections Influence Stretching of the Gastrocnemius Muscle-Tendon Unit in an Animal Model

“…Volume and dose of BoNT-A were chosen to provide maximal denervation, and all biomechanical assessments were performed eight days following injection to reach maximal denervation based upon previous dose-volume experimentation in our laboratory using this animal model system [17,20]. …”

“…BoNT-A is endocytosed by the distal neuron and prevents the pre-synaptic vesicular fusion mediated by SNARE proteins (synaptobrevin, syntaxin, and synaptosomal-associated protein-25) and thus the release of acetylcholine at the neuromuscular junction inhibiting normal synaptic transmission and neural-mediated muscle contraction [5]. Injection of BoNT-A induces a temporary and reversible paresis of skeletal muscle with a decrease of motor action potential (CMAP) of up to 80% one week after injection depending on dose and volume applied [17]. The adjunctive application of BoNT-A to physical therapy of patients with muscle spasticity has been shown to improve clinical outcomes and decrease symptoms [5].…”