4-aminopyridine-3-methanol and Disease-Models--Animal

Motor recovery after severe spinal cord injury (SCI) is limited due to the disruption of direct descending commands. Despite the absence of brain-derived descending inputs, sensory afferents below injury sites remain intact. Among them, proprioception acts as an important sensory source to modulate local spinal circuits and determine motor outputs. Yet, it remains unclear whether enhancing proprioceptive inputs promotes motor recovery after severe SCI. Here, we first established a viral system to selectively target lumbar proprioceptive neurons and then introduced the excitatory Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADD) virus into proprioceptors to achieve specific activation of lumbar proprioceptive neurons upon CNO administration. We demonstrated that chronic activation of lumbar proprioceptive neurons promoted the recovery of hindlimb stepping ability in a bilateral hemisection SCI mouse model. We further revealed that chemogenetic proprioceptive stimulation led to coordinated activation of proprioception-receptive spinal interneurons and facilitated transmission of supraspinal commands to lumbar motor neurons, without affecting the regrowth of proprioceptive afferents or brain-derived descending axons. Moreover, application of 4-aminopyridine-3-methanol (4-AP-MeOH) that enhances nerve conductance further improved the transmission of supraspinal inputs and motor recovery in proprioception-stimulated mice. Our study demonstrates that proprioception-based combinatorial modality may be a promising strategy to restore the motor function after severe SCI.

Topics: Aminopyridines; Animals; Combined Modality Therapy; Dependovirus; Disease Models, Animal; Female; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Mice; Motor Neurons; Neural Conduction; Proprioception; Recovery of Function; Spinal Cord Injuries

To evaluate the effects of 4-aminopyridine-3-methyl hydroxide (4-AP-3-MeOH) in rat's acute spinal cord injury.. A total of 12 adult male SD rats (250-300 g) were randomly divided into treatment (n = 6) and control (n = 6) groups. After compressing segment T11 of spinal cord for 30 min, the injured segment received 1 ml 4-AP-3-MeOH (100 µmol/ml) by topically application in treatment group while the control group received 1 ml saline.Somatosensory evoked potential (SSEP) was detected in both groups at pre-injury, 30 min post-injury and post-dosing. Then Luxol fast blue (LFB) staining of target spinal segment was performed.. In treatment group, the values of SSEP at pre-injury, 30 min post-injury and post-dosing were 1.26 ± 0.35, 0.03 ± 0.05 and 0.45 ± 0.19 µv respectively. Comparing SSEP of 30 min post-injury with post-dosing, the difference was statistically significant (P < 0.01).While in control group, the values of SSEP at pre-injury, 30 min post-injury and post-dosing were 1.05 ± 0.39, 0.01 ± 0.02 and 0.02 ± 0.02 µv respectively. Comparing SSEP of 30 min post-injury with post-dosing, there was no statistical difference (P > 0.05). After 30 min injury, there were swelling and bleeding of spinal cord.LFB staining showed that both gray and white matter had swelling and bleeding and central canal was destroyed with varying degrees of demyelination.. After 30 min of acute spinal cord injury, there are bleeding of gray and white matter with varying degrees of demyelination. Topical usage of K(+) blocker 4-AP-3-MeOH can effectively improve the conduction of SSEP after acute spinal cord injury in rats.

Topics: Aminopyridines; Animals; Disease Models, Animal; Male; Neural Conduction; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Compression

Multiple sclerosis (MS) is a severely debilitating neurodegenerative diseases marked by progressive demyelination and axonal degeneration in the CNS. Although inflammation is the major pathology of MS, the mechanism by which it occurs is not completely clear. The primary symptoms of MS are movement difficulties caused by conduction block resulting from the demyelination of axons. The possible mechanism of functional loss is believed to be the exposure of potassium channels and increase of outward current leading to conduction failure. 4-Aminopyridine (4-AP), a well-known potassium channel blocker, has been shown to enhance conduction in injured and demyelinated axons. However, 4-AP has a narrow therapeutic range in clinical application. Recently, we developed a new fast potassium channel blocker, 4-aminopyridine-3-methanol (4-AP-3-MeOH). This novel 4-AP derivative is capable of restoring impulse conduction in ex vivo injured spinal cord without compromising the ability of axons to follow multiple stimuli. In the current study, we investigated whether 4-AP-3-MeOH can enhance impulse conduction in an animal model of MS. Our results showed that 4-AP-3-MeOH can significantly increase axonal conduction in ex vivo experimental autoimmune encephalomyelitis mouse spinal cord.

Topics: Action Potentials; Aminopyridines; Animals; Axons; Disease Models, Animal; Glycoproteins; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Sheath; Myelin-Oligodendrocyte Glycoprotein; Neural Conduction; Neurofilament Proteins; Peptide Fragments; Potassium Channel Blockers; Reaction Time; Spinal Cord