Pharmacological stimulation to facilitate and restore standing and walking functions in spinal cord motor disorders
The invention relates to the selective targeting of specific α2 adrenergic receptor subtypes for facilitating and also restoring standing and walking in a subject affected by spinal cord disorders, in particular spinal cord injury. In particular, the improvement of locomotion by targeting specific receptor subtypes can be achieved by stimulation of the α2c receptor subtype using an α2c specific agonist or by blocking the α2a receptor subtype using α2a antagonists. A combination of an α2c agonist and an α2a antagonist is also provided for a synergistic effect. Alternatively, a large α2 agonist can be used in combination with an α2a antagonist to achieve specific stimulation of the α2c receptor. Pharmaceutical compositions, kit-of-parts and therapeutic systems comprising said agonists/antagonists as active agents are objects of the present invention. A robotic interface and epidural electric stimulation can also be used in combination with the compositions of the invention for restoring voluntary control of locomotion.
1. A method for improving motor functions in a subject affected by a spinal cord injury, comprising a step of selectively targeting α2 adrenergic receptor subtypes selected from the group of α2c and α2a via administering a pharmaceutical composition comprising at least one molecule activating an α2c adrenergic receptor subtype and at least one molecule blocking an α2a adrenergic receptor subtype to the subject, wherein the at least one molecule activating the α2c adrenergic receptor subtype does not include a non-specific α2 agonist, to improve the motor functions of the subject, wherein said at least one molecule activating the α2c adrenergic receptor subtype is selected from the group consisting of (R)-3-Nitrobiphenyline and a compound of formula (I);
wherein improving the motor functions in the subject includes facilitating locomotion in the subject, the method further comprising a step of using a robotic interface capable of evaluating, enabling, and training motor pattern generation and balance to restore voluntary control of locomotion in the subject; and
wherein the foregoing steps are performed simultaneously, sequentially, or in any desired order.
2. The method according to claim 1 , wherein the at least one molecule blocking an α2a adrenergic receptor subtype to the subject is an α2a antagonist BRL-44408.
3. The method according to claim 1 , wherein said composition further comprises a 5-HT1 and/or 5-HT7 serotonergic agonist.
4. The method according to claim 1 , wherein said composition is in injectable form.
5. The method according to claim 1 , further comprising a step of providing epidural electrical stimulation;
wherein the foregoing steps are performed simultaneously, sequentially, or in any desired order.
6. The method according to claim 1 , wherein facilitating locomotion in the subject includes facilitating stepping.
7. The method according to claim 1 , wherein the spinal cord injury includes an impaired or totally hindered capacity of standing and walking.
8. The method according to claim 1 , wherein the step of selectively targeting α2 adrenergic receptor subtypes and the step of using a robotic interface are initiated after a recovery period of 2-5 weeks after the spinal cord injury.