Methods for treating diabetic neurotherapy
Provided are methods for promoting axon regeneration of a Central Nervous System (CNS) neuron and promoting nerve function following injury to a CNS neuron, for example, brain and/or spinal cord injury. Axon regeneration in a CNS neuron or nerve function following injury to a CNS neuron can be promoted by administering a necrosis inhibitor either alone or in combination with an apoptosis inhibitor to a subject suffering from a CNS disorder, wherein a symptom of the CNS disorder is axon degeneration.
1. A method for treating diabetic neuropathy in a subject in need thereof by promoting axon regeneration in a CNS neuron, the method comprising:
exposing the CNS neuron of the subject to an effective amount of a necrostatin and an effective amount of an apoptosis inhibitor thereby to promote the regeneration of the axon of the CNS neuron;
wherein the necrostatin is selected from the group consisting of:
(i) a Nec-1 related compound of Formula I:
or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
X is O or S;
R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or halogen; and
R 2 is hydrogen or C 1 -C 6 alkyl;
(ii) a Nec-1 related compound of Formula I-A:
or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
R 1 is H, alkyl, alkoxyl, or a halogen and
R 2 is H or an alkyl;
(iii) a Nec-1 related compound of Formula I-B:
or a pharmaceutically acceptable salt, ester, or prodrug thereof;
(iv) a Nec-1 related compound of Formula I-C:
or a pharmaceutically acceptable salt, ester, or prodrug thereof;
(v) a Nec-1 related compound of Formula I-D:
or a pharmaceutically acceptable salt thereof;
(vi) a Nec-1 related compound of Formula I-E:
or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
R 1 is H, alkyl, alkoxyl, or a halogen and
R 2 is H or an alkyl;
(vii) a Nec-1 related compound of Formula I-F:
or a pharmaceutically acceptable salt, ester, or prodrug thereof; and
(viii) a Nec-1 related compound of Formula I-G:
or a pharmaceutically acceptable salt, ester, or prodrug thereof; and
wherein the apoptosis inhibitor is a pan-caspase inhibitor, a caspase-1 inhibitor, a caspase-2 inhibitor, a caspase-3 inhibitor, a caspase-4 inhibitor, a caspase-5 inhibitor, a caspase-6 inhibitor, a caspase-7 inhibitor, a caspase-8 inhibitor, a caspase-9 inhibitor, or a combination thereof.
2. The method of claim 1 , wherein the neuron is ex vivo.
3. The method of claim 1 , wherein the neuron is in vivo.
4. The method of claim 1 , wherein the CNS neuron is selected from the group consisting of a sensory neuron, a motor neuron, a cortical neuron, a pyramidal neuron, a cerebellar neuron, a hippocampal neuron, and a midbrain neuron.
5. The method of claim 1 , wherein the necrostatin is necrostatin 1.
6. The method of claim 1 , wherein from about 0.05 mg to about 2 mg of the necrostatin is administered.
7. The method of claim 1 , wherein the apoptosis inhibitor is a pan-caspase inhibitor.
8. The method of claim 7 , wherein the pan-caspase inhibitor is zVAD, IDN-6556 or a combination thereof.
9. The method of claim 1 , wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered locally.
10. The method of claim 1 , wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered systemically.
11. The method of claim 1 , wherein the necrostatin and the apoptosis inhibitor are administered sequentially or simultaneously.