A team of researchers from Nanjing Medical University in China has synthesized a compound that opens a new avenue for fighting depression. It’s called ZZL-7 and it induces a response in just two hours in mice that serve as a model for major depressive disorder. Also, no apparent side effects.
This speed of action is important because current antidepressants, such as fluoxetine (active ingredient behind the famous drug Prozac), take about four weeks to show effects.
This is not the only problem with the current pharmaceutical arsenal, as they have negative side effects and only part of the drugs manage to recover from depression. For this reason, these drugs are in the sights of many professionals. Even the hypothesis on which they are based (lack of serotonin in the brain) has recently been called into question.
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The finding of the Nanjing team, led by Nan Su, from the university’s School of Pharmacy, has been published in Science. Although there are still many steps for this ZZL-7 to be tested in people, the path opened by the researchers seems solid.
New antidepressant drugs
The new drug – which, the scientists point out, is a small and easy-to-synthesize molecule, which would be a great advantage – interrupts the interaction between serotonin transporters (called SERT, the target of classic antidepressants) and neuronal nitric oxide synthase (nNOS), reducing intercellular serotonin levels in a region of the brain known as the dorsal raphe nucleus.
The researchers have verified that, by doing this, they manage to improve the serotonergic activity of the neurons in this area and increases serotonin release in the medial prefrontal cortex.
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The authors administered the compound intravenously to mice that had been exposed, in the previous 28 days, to mild chronic stress. Within two hours of administration, ZZL-7 had reversed the SERT-nNOS complex in the dorsal raphe nucleus and stress-related depressive behaviors. The effect persisted for the next 24 hours.
The molecule was already detectable in the dorsal raphe nucleus within half an hour of administration, indicating that had been able to cross the blood-brain barrier, a natural ‘border’ of the brain that prevents the passage of foreign elements. Crossing it is one of the great challenges in the development of drugs aimed at neurological problems, such as Alzheimer’s disease or Parkinson’s.
Furthermore, using mass spectrometry, Nan Sun and his team found that the drug had also been able to penetrate the cell membrane.
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There are currently several alternatives to classic antidepressants that are in various stages of development. Esketamine, for example, has already been approved by regulatory agencies (including the Spanish one) and promises to improve depressive symptoms in more than 70% of patients in a matter of hours.
The problem associated with this drug is its addictive potential (in fact, it is used as a recreational drug) and the risk of schizophrenia. Another alternative is psilocybin, based on a hallucinogenic mushroom popular in the 1960s and currently in clinical trials. It would also offer a quick and prolonged response, but its administration must take place in controlled environments under the supervision of experienced specialists.
According to Nan Sun and colleagues, ZZL-7 has not caused any significant adverse events in the mice used. It has no effect on locomotor or general activity, nor on memory or cognition. In addition, it does not induce aggressive behaviors or generate abnormal brain waves.
“Our results suggest that ZZL-7 should be developed as a new rapid-onset antidepressant candidate,” they conclude.
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