Abstract
An in-depth review of Cortexin, the polypeptide complex derived from bovine/porcine brain cortex, covering its composition, neuroprotective mechanisms, Russian clinical evidence in stroke and neurodevelopmental disorders, and relationship to Pinealon.
Cortexin is a complex polypeptide preparation derived from the cerebral cortex of cattle or pigs through controlled enzymatic hydrolysis and purification. Developed in Russia at the Institute of Bioregulation and Gerontology under the direction of Vladimir Khavinson, Cortexin contains a mixture of low-molecular-weight neuropeptides (predominantly below 10,000 daltons), vitamins, amino acids, and trace minerals that collectively exert neuroprotective, neurotrophic, and antioxidant effects on the central nervous system. The preparation has been widely used in Russian clinical medicine since its registration in 1999, with primary indications including ischemic stroke, traumatic brain injury, cognitive disorders, and certain neurodevelopmental conditions in children.
The composition of Cortexin reflects the complex peptidome of the cerebral cortex. Proteomic analysis has identified fragments of multiple brain-specific proteins including synaptophysin, neurofilament proteins, myelin basic protein, tubulin, and various neuropeptides. Of particular significance, the bioactive tripeptide Pinealon (Glu-Asp-Arg) was identified as one of the key active components of Cortexin, later synthesized independently for therapeutic use. Similarly, other short peptide bioregulators including Cortagen (a tetrapeptide) were isolated from Cortexin. This relationship between the parent complex and its constituent peptides is central to the Khavinson school of bioregulatory peptide therapy.
The mechanism of action of Cortexin involves multiple parallel neuroprotective pathways. The preparation enhances the expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in neural tissue, supporting neuronal survival and synaptic plasticity. It modulates neurotransmitter balance, optimizing the ratio between excitatory (glutamate) and inhibitory (GABA) neurotransmission, which is frequently disrupted in neurological injury. Cortexin has been shown to normalize the bioelectrical activity of the brain, with clinical EEG studies demonstrating increased alpha rhythm power and reduced pathological slow-wave activity following treatment.
The antioxidant properties of Cortexin are mediated through upregulation of endogenous antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase. These enzymatic defenses are critical for protecting neurons from oxidative damage, which plays a central role in ischemic stroke, neurodegenerative diseases, and traumatic brain injury. Additionally, Cortexin reduces lipid peroxidation and protects mitochondrial function under oxidative stress conditions.
Anti-apoptotic effects represent another important mechanism. Cortexin inhibits caspase-3 activation—the final executioner enzyme in the apoptotic cascade—and modulates the balance between pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) proteins in favor of cell survival. This mechanism is particularly relevant in the peri-infarct penumbra zone of ischemic stroke, where neurons are under stress but potentially salvageable.
Clinical research with Cortexin in ischemic stroke constitutes its largest evidence base. Multiple clinical trials in Russia have demonstrated that intramuscular Cortexin at 10 mg per day for 10 days, initiated in the acute phase of ischemic stroke, significantly improves neurological recovery compared to standard therapy alone. Studies document faster resolution of neurological deficits, improved cognitive recovery, reduced disability scores, and enhanced quality of life outcomes. A large observational study involving over 1,500 stroke patients confirmed the safety and efficacy of Cortexin as an adjunctive treatment for acute and rehabilitative stroke care.
In traumatic brain injury, clinical studies have shown that Cortexin improves cognitive recovery, reduces post-traumatic headache severity, normalizes EEG patterns, and accelerates return to functional independence. The neuroprotective effects are attributed to the combination of anti-inflammatory, antioxidant, and neurotrophic mechanisms that collectively limit secondary brain damage and promote neural repair.
Pediatric applications represent a distinctive aspect of Cortexin's clinical profile. The preparation has been used extensively in Russian pediatric neurology for conditions including cerebral palsy, delayed psychomotor development, speech disorders, attention deficit disorders, and consequences of perinatal hypoxic-ischemic brain injury. Clinical studies in children have reported improvements in motor function, cognitive development, speech acquisition, and behavioral parameters. A study in 62 children with perinatal encephalopathy demonstrated that Cortexin treatment improved cognitive scores, normalized EEG patterns, and enhanced motor milestones.
The relationship between Cortexin and its synthetic derivatives (Pinealon, Cortagen) is important for understanding the evolution of bioregulatory peptide therapy. Cortexin represents the first-generation approach: a complex biological extract containing the full spectrum of cortical peptides. Pinealon and Cortagen represent the second-generation approach: defined synthetic peptides isolated from the parent complex and manufactured to pharmaceutical purity. The synthetic derivatives offer advantages of defined composition, batch-to-batch consistency, and elimination of biological origin risks, while potentially sacrificing the synergistic interactions among the multiple components present in the parent complex.
Safety data from extensive Russian clinical use indicate that Cortexin is generally well tolerated. The most common adverse effect is injection site pain. Systemic side effects are rare and include transient headache, mild dizziness, and occasional allergic reactions. Serious adverse events are very uncommon. Contraindications include known hypersensitivity to Cortexin or animal-derived proteins and pregnancy (due to insufficient safety data). Unlike Cerebrolysin, Cortexin has not been associated with seizure exacerbation, though caution in epilepsy patients is still recommended.
Cortexin is registered as a pharmaceutical drug in Russia and several CIS countries. It is not approved in Western jurisdictions (FDA, EMA) and is not available internationally through standard pharmaceutical channels. Its clinical evidence base, while substantial in volume, is predominantly from Russian single-center studies that may not meet the methodological rigor expected for Western regulatory approval.
