Current and future medical therapeutic strategies for the functional repair of spinal cord injury

Table 1 Secondary ınjury mechanisms involved in the pathophysiology of spinal cord injury

Systemic effects

Heart rate - brief increase then prolonged bradycardia

Blood pressure - brief hypertension then prolonged hypotension

Peripheral resistance - decreased

Cardiac output - decreased

Local vascular damage of the cord microcirculation

Mechanical disruption of capillaries and venules

Hemorrhage - especially gray matter

Loss of microcirculation - mechanical, thrombosis, vasospasm

Biomechanical changes

Excitotoxicity - glutamate

Neurotransmitter accumulation

Catecholamines - noradrenaline, dopamine

Arachidonic acid release

Free radical production

Eicosanoid production

Prostaglandins

Lipid peroxidation

Endogenous opioids

Cytokines

Electrolyte shifts

Increased intracellular calcium

Increased intracellular potassium

Increased intracellular sodium

Inflammatory response

Free radical generation

Macrophages

Axonal breakdown, removal of myelin debris

Release of cytokines

Glial cell activation

Cytotoxic effects on oligodendrocytes

Wallerian degeneration

Edema

Apoptosis

Loss of energy Metabolism

Decreased ATP production

SCI: Spinal cord injury.

Table 2 American spinal ınjury association ımpairment scale

A = Complete: No motor or sensory function is preserved in the sacral segments

B = Incomplete: Sensory but not motor function is preserved below the neurological level and includes sacral segments

C = Incomplete: Motor function preserved below the neurological level; more than half the key muscles below the neurological level have a muscle grade less than 3

D = Incomplete: Motor function preserved below the neurological level; at least half the key muscles below the neurological level have a muscle grade of 3 or more

E = Normal: Motor and sensory function

Table 3 Pharmacotherapy of acute spinal cord injury and mechanism(s) of action

Methylprednisolone

Inhibition of lipid peroxidation/antioxidative/anti-inflammatory

Properties decrease ischemia, support energy metabolism, inhibit neurofilament degradation, decrease intracellular Ca, decrease PG F/ TxA, increase spinal neuron excitability, decrease cord edema

Ganglioside GM-1

Stimulate neurite regrowth/regeneration

Opioid receptor antagonists

Antagonize the increase in endogenous opioid levels after SCI (opioid receptor activation can contribute to excitotoxicity)

TRH and its analogs

Antagonize endogenous opioids, platelet-activating factor, peptido- leukotrienes and excitatory amino acids

Nimodipine

Decrease intracellular Ca2+ accumulation, attenuate vasospasm

Gacyclidine (GK11)

Antagonism of glutamate receptors

Magnesium

Replace Mg2+ depletion that is common after SCI, diminish intracellular Ca2+ accumulation, block N-methyl-D-aspartate receptor ion channel, modulate binding of endogenous opioids

Hypothermia

Reduce extracellular glutamate, vasogenic edema, apoptosis, neutrophil and macrophage invasion and activation, and oxidative stress

Minocycline

Inhibition of microglial activation, inhibition of cytochrome c release

Erythropoietin

Reduced apoptosis and lipid peroxidation

Estrogen

Not clearly known

Progesterone

Reduce the production of inflammatory cytokines

Cyclooxygenase inhibitors

Prevents/antagonizes decreased blood flow/platelet aggregation from production of arachidonic acid metabolites

Riluzole

Blockade of voltage-sensitive sodium channels and antagonism of presynaptic calcium-dependent glutamate release

Atorvastatin

Prevents neuronal and oligodendrocytic apoptosis

Antioxidants

Antagonize deleterious effects of free radicals (lipid eroxidation, reperfusion injury, etc.)

PG F: Prostaglandin F; SCI: Spinal cord injury.

Table 4 Cellular transplantatıon therapıes spinal cord injury

Schwann cells	Secrete growth factors, reestablish microenvironment
Olfactory ensheathing cells	Promoting axonal regeneration
Bone marrow cells	Produce neuroprotective cytokines
Stimulated macrophages	Removal of myelin debris, release of cytokines
Oligodendrocyte progenitor cells	Achieve remyelination

Table 5 Timing of surgery and nonsurgical treatment options of spinal cord injury including pharmacological and cellular therapy

Timing of surgery

Early surgical intervention is safe and feasible which can improve clinical and neurological outcomes and reduce health care costs

Early surgical intervention helps minimize the secondary damage caused by compression of the spinal cord after trauma

Pharmacological and cellular therapy

There is still no accepted pharmacological treatment protocol in SCI

Methylprednisolone is the accepted agent used in SCI, however, some criticism has been reported by some authors. It might be used in young patients without accompanying diseases such as diabetes mellitus

Cellular treatment studies are continuing

SCI: Spinal cord injury.