Riluzole, a Novel Neuroprotective Agent, Attenuates Both Neurologic Motor and Cognitive Dysfunction Following Experimental Brain Injury in the Rat

Abstract

Several potential mechanisms are involved in mediating the pathophysiology of traumatic brain injury (TBI), including inflammatory processes and excitotoxicity. In the present study, we evaluated the ability of the use-dependent sodium channel inhibitor Riluzole to attenuate cognitive and neurologic motor deficits and reduce regional cerebral edema and histologic cell damage following lateral fluid-percussion (FP) brain injury in rats (n = 109). In study 1, 58 anesthetized male Sprague-Dawley rats (350-400 g) were subjected to FP brain injury of moderate severity (2.3-2.5 atm). Fifteen minutes following brain injury, animals randomly received an i.v. bolus of either Riluzole (4 mg/kg, n = 11), Riluzole (8 mg/kg, n = 11), or glycol vehicle (n = 20), followed by 6 h and 24 h s.c. injections (identical dose). Surgically prepared but uninjured animals received vehicle (n = 16) and served as controls. Animals were evaluated for cognitive deficits at 48 h postinjury and killed for assessment of regional brain edema. Administration of vehicle or Riluzole (4 mg/kg x 3) had no significant effect on memory or edema, whereas Riluzole (8 mg/kg x 3) significantly attenuated post-traumatic cognitive dysfunction (p < 0.05). In study 2, a second group of animals (n = 25) was injured, treated with Riluzole (8 mg/kg x 3 doses, n = 13) or vehicle (n = 12), and evaluated for neurologic motor function over 2 weeks. Animals treated with Riluzole demonstrated significantly improved motor scores beginning 1 week postinjury (p < 0.05). In study 3, brain-injured animals were treated with Riluzole (8 mg/kg x 3 doses, n = 10) or vehicle (n = 10), and posttraumatic lesion volume was assessed at 48 h postinjury using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Treatment with Riluzole had no significant effect on posttraumatic lesion volume. The present study demonstrates that use-dependent sodium channel inhibitors, such as Riluzole, can attenuate both cognitive and neuromotor dysfunction associated with brain trauma.

Delayed Post-Injury Administration of Riluzole Is Neuroprotective in a Preclinical Rodent Model of Cervical Spinal Cord Injury

“…Others have also reported that riluzole at the above dose reduces the extent of cellular damage and neurobehavioral deficits following trauma in rodents. 32 As the repeated injection of 8 mg/kg was shown to be toxic in our initial findings, the subsequent doses were reduced to 6 mg/kg. The reduced dose of 6 mg/kg resulted in significantly fewer side effects and less toxicity.…”

Effect of Riluzole on Cytosolic Ca²⁺ Increase in Human Osteosarcoma Cells

“…It has been shown that riluzole activates K + channels [5,6], inhibits Cl -channels [7], blocks glutamate transmission [8][9][10], stabilizes Na + channels [11] and inhibits Á-aminobutyric acid reuptake [12][13][14]. Additionally, riluzole was shown to attenuate neurotoxicity in brain preparations and an animal model [15][16][17][18]. Evidence has accumulated showing that riluzole blocks neurosecretion [19][20][21][22] and increases glutamate uptake [23].…”

Future Directions for Therapy of Childhood Hydrocephalus: A View from the Laboratory

“…The beneficial effect is most likely through an improvement in blood flow. Similar treatment of hydrocephalic rats with the sodium channel blocking agents mexiletine and riluzole, both of which have neuroprotective effects under some conditions [146, 147], were not obviously effective (unpubl. data).…”