PE-22-28

PE-22-28: A Potential Breakthrough in Depression Treatment Research conducted in mouse models of depression has revealed that PE-22-28 holds remarkable efficacy in alleviating depression symptoms, surpassing the effectiveness of currently employed treatments while exhibiting fewer side effects. Notably, PE-22-28 has demonstrated the capacity to relieve depression in just four days without affecting other functions regulated by the TREK-1 channel.

Depression is often associated with a reduced volume of the hippocampus, a critical brain region. Long-term use of conventional antidepressants has been shown to promote neurogenesis in the hippocampus, resulting in increased hippocampal volume. PE-22-28’s ability to stimulate neurogenesis and reverse this volume loss suggests that it addresses depression at its core and may help unveil some of the underlying physiological pathways involved in depression.

The lack of side effects associated with spadin and PE-22-28 is of paramount importance. Current depression treatments are notorious for their array of side effects, ranging from suicidal tendencies to altered libido and cognitive impairments. Even ketamine, which has gained attention as a rapid-onset depression treatment, comes with a host of side effects, including delirium, hallucinations, muscle tremors, high blood pressure, and increased heart rate. Consequently, the utilization of ketamine for depression treatment has been met with hesitation due to the severity and diversity of its side effects.

Initially, concerns were raised about potential side effects of spadin and PE-22-28, as the TREK-1 receptor has been implicated in pain sensitivity, seizure activity, and cardiac ischemia. Moreover, there were apprehensions about whether spadin and PE-22-28 might inhibit currents in other potassium channels like TREK-2, TRAAK, TASK, and TRESK, leading to additional side effects. However, research in mice has demonstrated the absence of these side effects, with PE-22-28 exhibiting one of the most minimal side effect profiles among existing and experimental depression treatments.

Addressing Post-Stroke Depression (PSD) Post-stroke depression (PSD) often follows brain ischemia and proves challenging to treat using standard methods. Recent research suggests that overexpression of TREK-1 contributes to PSD. In mouse models, this upregulation can be mitigated or reversed using selective serotonin reuptake inhibitors (SSRIs) and TREK-1 blockers like spadin. Notably, SSRIs take significantly longer to exert their effects and are associated with a variety of side effects. This implies that PE-22-28 may hold promise as a potential treatment for PSD in future trials.

Neurogenesis Enhancement Antidepressant drugs are known for their capacity to stimulate neurogenesis in the hippocampus. Research has shown that PE-22-28 can achieve a similar outcome but in a much shorter timeframe. Studies in mice indicate that after just four days of PE-22-28 administration, both neurogenesis and synaptogenesis are significantly increased. Preliminary data suggests that PE-22-28 approximately doubles the number of BrdU-positive cells in the hippocampus. Furthermore, it appears to double the rate of synapse formation.

A potential clue to PE-22-28’s impact on brain cell division lies in its ability to elevate CREB levels. CREB (cAMP response element-binding protein) is a transcription factor linked to neuronal plasticity, memory formation, and spatial memory development. Notably, CREB has been implicated in neuronal growth and protection, particularly in the context of Alzheimer’s disease. PE-22-28 is actively under investigation for its potential to prevent and reverse Alzheimer’s symptoms.

The hippocampus, in addition to its role in depression, is crucial for learning, memory, and spatial navigation. This plastic brain structure is vulnerable to damage from various insults, and enhancing its regenerative abilities could hold promise in treating multiple diseases. Notably, the hippocampus’s involvement in cognition suggests that PE-22-28 or a similar TREK-1 antagonist may have potential as a nootropic.

While removing the TREK-1 channel in animal models has been linked to detrimental consequences such as increased seizure activity and reduced neuroprotective effects, spadin and PE-22-28 do not exacerbate seizure activity. In fact, mice treated with spadin exhibit increased resistance to generalized seizures. PE-22-28 demonstrates even more substantial protective effects compared to spadin.