*3.1.9 Metformin*

Metformin is a hypoglycemic agent used for therapy of type 2 diabetes mellitus; it is an AMP-activated protein kinase (AMPK) agonist. Metformin also acts through signaling pathway of mTOR and p70S6K causing an inhibition of apoptosis and inflammation. This drug is also capable of stimulating autophagy and reducing expression of NF-kB-mediated inflammation [73, 74]. Studies indicate that long-term use of metformin has been proved effective as a pharmacological treatment for some CNS disorders like Parkinson's disease, Huntington's disease, and ischemic brain injury. Using a rat model of traumatic SCI, the administration of metformin helps restoring the dysfunctional autophagy-lysosome pathways providing neuroprotection, decreasing neuronal death and mitigating apoptosis [75, 76]. The immediate administration of metformin after the injury showed diminishing complications, reflecting a decrease on histopathological signs of neuroinflammation, including TNFα and IL-1β inflammatory cytokines in the SC [73]. Although these outcomes are promising, subsequent studies are required to determine the risk ad optimal doses for the use of metformin on clinical studies.

#### *3.1.10 Gonadal hormones*

Androgens and estrogens are multi-active steroidal hormones that have neuroprotective effects in neural injuries; both testosterone and estradiol improve safeguard against apoptosis and promote motor and sensitive recovery. Also, reduce inflammation and FR generation and have been involved in regulating the expression of cytoskeletal proteins, promoting them as an increasing in neurite outgrowth [77, 78]. Studies in rats treated with estradiol have shown a reduction in the lesion size, an increase in white matter sparing, and an improving in motor function [77, 79, 80]. On the other hand, testosterone has shown to exert similar but not identical effects; it is neuroprotective against apoptosis in oxidative stress [77, 78]. A study with young adult female rats implanted with testosterone-filled silastic capsules reported regressive changes in motoneuron and muscle morphology after a SCI providing the possibility of improving motor function [81]. A study with administration of progesterone in rats improves neurological deficits and reduces inflammatory response. Prevents degeneration of motor neurons and reestablishes proliferation and differentiation of oligodendrocytes [82]. At the moment, investigations on the field conclude that gonadal hormones could be an effective alternative after SCI.
