Sovateltide for the Treatment of Acute Traumatic Brain Injury

A traumatic brain injury (TBI) is a form of brain damage that results from an external mechanical force impacting the head or body, such as a sudden blow, jolt, or wound. The injuries could be penetrating (open) ones - commonly seen in motor vehicle accidents, falls, sports injuries, and explosive blasts in which an object such as a bullet, shrapnel, or bone fragment breaches the skull and directly damages brain tissue, or non-penetrating (closed or blunt) ones, which result from rapid acceleration, deceleration, or rotational forces that cause the brain to move within the skull. Based on the timing of the impact and damage, these injuries are categorized as primary or secondary. Primary injuries, such as contusions, lacerations, or hemorrhage, occur at the moment of impact and involve immediate damage. Secondary injury develops over time through complex biochemical and physiological processes such as increased intracranial pressure, cerebral edema, ischemia, excitotoxicity, oxidative stress, and neuroinflammation, which can worsen neurological outcomes later.

According to the Global Burden of Diseases database in 2021, there were 20.84 million incident cases and 37.93 million prevalent cases of TBI worldwide. Between 1990 and 2021, the global number of TBI incidents and prevalent cases increased by 22.6% and 53.3%, respectively; however, the age-standardized incidence rate declined by 0.11%. These rates generally increased with age and were higher in males than in females. The highest age-standardized prevalence and years lived with disability rates were observed in Eastern and Central Europe. Globally, falls were the leading cause of TBI in 2021, followed by road injuries, violence, and exposure to mechanical forces.

Currently, no therapeutic agent is approved for TBI because of the injury's biological complexity, heterogeneity in patient presentation, and limited translation of preclinical success into human trials. Hence, future progress likely depends on developing drugs or combination therapies with multimodal mechanisms of action that support neural cell protection, regeneration, repair, and functional restoration. Moreover, TBI pathophysiology is complex, involving vascular damage, inflammation, apoptosis, and other processes that trigger neuronal damage and death. A thorough understanding of TBI pathophysiology is essential for developing novel therapeutic agents that provide neuroprotection by curbing inflammation, enhancing angiogenesis, reducing hypoxic episodes, excitotoxicity, and apoptosis, and promoting neuroregeneration in injured brain tissue. Endothelin signaling regulates these pathophysiological events in the mammalian neurovascular system; therefore, the endothelin system could be a potent drug-development target in TBI.

Sovateltide (TycamzziTM, IRL-1620, PMZ-1620) is a first-in-class ETB receptor agonist approved in India for treating acute ischemic stroke (AIS), promoting neuroprotection and regeneration via neuron and blood vessel growth. We evaluated the neuroprotective potential of sovateltide in the Marmarou weight-drop rat model of traumatic brain injury (TBI). TBI onset in rats damaged blood-brain barrier (BBB) and increased brain water content, inflammation and oxidative stress. Neuronal damage in the prefrontal cortex and hippocampal subfields (CA1-CA3 and dentate gyrus) was seen on day 1 post-injury. A marked increase in Neurobehavioral Severity Score-Revised (NSS-R), indicating neurological impairment, was also observed. Rats were either treated with sovateltide (5μg/kg) or mannitol (20% w/v) or Normal Saline (5ml/kg) administered three times a day on 1st, 3rd and 6th day after induction of TBI. Animals treated with sovateltide or mannitol showed progressive functional recovery with a significantly reduced NSS-R score compared to untreated TBI rats by day 7. These animals also showed a clear trend toward behavioral improvement; however, anxiety levels and locomotor activity remained comparable. Damage to the BBB, reflected by elevated Evans Blue Dye elution, was substantially reduced in sovateltide-treated rats. Sovateltide exhibited antioxidant activities and reduced malondialdehyde (MDA) levels, restoring superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels to near-normal. Sovateltide-treated rats had decreased inflammatory indicators/mediators (e.g., NF-κB, IL-6, and TNF-α) compared with untreated and mannitol-treated animals. At the tissue level, sovateltide-treated animals had better-preserved neural tissue architecture, like sham animals, than control and mannitol-treated animals. Apoptotic markers caspase-3 and caspase-6 were significantly reduced in sovateltide animals, along with attenuation of astrocytic activation indicated by decreased GFAP in cortical and hippocampal regions. Thus, sovateltide confers multimodal neuroprotection by alleviating oxidative stress, suppressing neuroinflammation, preserving BBB integrity and neuronal morphology, and inhibiting apoptosis following TBI.

A TBI study in Wistar rats found that sovateltide preserved BBB integrity and reduced apoptosis, as evidenced by decreased caspase-3 and caspase-6 expression and improved neurobehavioral outcomes, likely due to its antioxidant and anti-apoptotic properties. Overall, studies show that the endothelin system, particularly ETB receptor signaling, represents a promising therapeutic axis that can address TBI heterogeneity by integrating vascular protection, anti-inflammatory effects, and neural regeneration. Unlike traditional monotherapies that target isolated pathways, ETB activation through sovateltide would offer a multimodal approach to target the full spectrum of TBI, from acute neuroprotection to long-term neural repair.

• Sovateltide stimulates ETB receptors, which are highly expressed during neural development. Research indicates that activating these receptors in the adult brain enhances NPC proliferation and differentiation into mature, functional neurons.
• Effective neurogenesis requires a robust blood supply. Sovateltide promotes the formation of new micro-vessels (angiogenesis) by increasing levels of Vascular Endothelial Growth Factor (VEGF) and Nerve Growth Factor (NGF). This ensures that the "new" brain tissue has the oxygen and nutrient support needed to survive and integrate.
• Sovateltide has been shown to inhibit the pathways that lead to delayed neuronal death. Protecting existing neurons in the "penumbra" (the area surrounding the core injury) limits the eventual size of the brain lesion.
• Research suggests that Sovateltide enhances mitochondrial biogenesis and maintains mitochondrial membrane potential. Since TBI causes massive metabolic failure, stabilizing the cell's "powerhouse" is critical for preventing further tissue loss.
• Stimulation of ETB receptors on the vascular endothelium triggers the release of nitric oxide, leading to vasodilation and improved perfusion to the injured regions.

The pathophysiological similarities between stroke and TBI-specifically the roles of ischemia, inflammation, and the need for remodeling-provide a strong "proof of concept" for the application of sovateltide in TBI.