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Can Antibiotics Stop The Growth of New Brain Cells?

The discovery of penicillin in 1928 by Alexander Fleming was one of the greatest revolutions in the history of medicine. Since then, multiple molecules with antibiotic properties have been identified and the use of antibiotics has become generalized. But even though they can certainly save lives, antibiotics can also have serious adverse effects.

Most of those side-effects are widely known: allergic reactions, fever, nausea, or diarrhea, for example, the latter resulting from a disruption of the bacterial composition of the intestinal flora. The gut microbiota is an obvious secondary target of antibiotics, and the gut microbiota has been increasingly recognized as an important regulator of brain functions through the gut-brain axis, having been associated with the development of a number of neurological and mental diseases.

Therefore, it is possible that antibiotics, by unbalancing the gut microbiota, may also have an indirect impact on brain function, since a link between neurodegenerative diseases, neuropsychiatric disorders, neuroinflammation, and gut microbiota dysregulation has been established.

Adult neurogenesis in the hippocampus is also a key process for a regular function of the brain. It has an essential role in brain plasticity and cognitive function, particularly in memory and learning. The hippocampus is involved in many neurological and mental diseases, with decreased neurogenesis being a key element in many pathologies. Decreases in hippocampal neurogenesis can be induced by such factors as social isolation or chronic stress, for example, leading to mental disorders or neurodegenerative diseases. An improvement in neurogenesis, on the other hand, can be achieved through physical or cognitive activity.

But is there a connection between these processes? Can the gut microbiota influence neurogenesis in the hippocampus? If so, can antibiotics also affect neurogenesis though their effects on the gut microbiota? The answer to these questions is what a study recently published in Cell Reports set out to find.

Antibiotics, the gut microbiota and the brain

The gut microbiota has an important influence on the immune system and in our body’s response to infection or inflammation. This effect is not restricted to the gut – immune responses in other organs, namely in the brain, can also be regulated by the gut microbiota. Using mice treated with antibiotics, the authors of this work aimed to determine the impact of gut flora dysregulation on hippocampal neurogenesis. Results showed that antibiotic treatment could indeed decrease neurogenesis in the hippocampus, leading to deficits in memory retention.

Aiming to determine whether those deficits were reversible, and since exercise is known to potentiate neurogenesis, the effects of exercise on mice treated with antibiotics were evaluated. Furthermore, and given that the administration of probiotics can balance gut microbiota composition, treatment with probiotics was also tested.

Interestingly, when the normal content of the gut flora was restored, the deficits in neurogenesis were not completely reversed unless the mice also engaged in physical activity in a running wheel or received probiotics. Since the restoration of a normal intestinal flora per se was unable to restore neurogenesis levels, it is most likely not exclusively the lack of gut flora that determines neurogenesis levels; additional factors may also come into play. But the fact that probiotics can have a similar effect to that of exercise is a clear indication of the importance of the gut microbiota in the modulation of neurogenesis.

This study also investigated the potential role of Ly6Chi monocytes, a type of cell of the immune system, as messengers between the gut and the brain, as well as the effect of antibiotic-induced dysregulation of the gut microbiota on these cells. Antibiotics did indeed decrease the levels of monocytes. Furthermore, the elimination of these cells decreased neurogenesis. But the replenishment of monocytes to these mice was able to restore neurogenesis after antibiotic treatment. Importantly, both exercise and probiotic administration led to an increase in Ly6Chi monocytes in the brain, indicating that these cells may serve as a communication system between the gut and the brain, contributing to the stimulation of neurogenesis induced by probiotics in antibiotic-treated mice.

Nevertheless, these effects in mice treated with antibiotics can be driven by other mechanisms besides the levels of Ly6Chi monocytes. Neuronal progenitor cells may receive additional signals involving other mediators or other types of cells, including glial cells or neurons. Still, data indicates that Ly6Chi may have a crucial involvement in hippocampal neurogenesis. This establishes a new messaging system between the gut and the brain through the immune system, and again underlines the importance of the gut in brain function.

This study also highlights the detrimental effects that antibiotics can have on the brain. On the bright side, probiotic supplementation and exercise can counteract the devastating side effects of prolonged antibiotic treatment, which is actually good news.

References

Bercik P, & Collins SM (2014). The effects of inflammation, infection and antibiotics on the microbiota-gut-brain axis. Advances in experimental medicine and biology, 817, 279-89 PMID: 24997039

Deng, W., Aimone, J., & Gage, F. (2010). New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nature Reviews Neuroscience, 11 (5), 339-350 DOI: 10.1038/nrn2822

Möhle, L., Mattei, D., Heimesaat, M., Bereswill, S., Fischer, A., Alutis, M., French, T., Hambardzumyan, D., Matzinger, P., Dunay, I., & Wolf, S. (2016). Ly6Chi Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis Cell Reports, 15 (9), 1945-1956 DOI: 10.1016/j.celrep.2016.04.074

Petra, A., Panagiotidou, S., Hatziagelaki, E., Stewart, J., Conti, P., & Theoharides, T. (2015). Gut-Microbiota-Brain Axis and Its Effect on Neuropsychiatric Disorders With Suspected Immune Dysregulation Clinical Therapeutics, 37 (5), 984-995 DOI: 10.1016/j.clinthera.2015.04.002

Schwartz, M., Kipnis, J., Rivest, S., & Prat, A. (2013). How Do Immune Cells Support and Shape the Brain in Health, Disease, and Aging? Journal of Neuroscience, 33 (45), 17587-17596 DOI: 10.1523/JNEUROSCI.3241-13.2013

Spalding, K., Bergmann, O., Alkass, K., Bernard, S., Salehpour, M., Huttner, H., Boström, E., Westerlund, I., Vial, C., Buchholz, B., Possnert, G., Mash, D., Druid, H., & Frisén, J. (2013). Dynamics of Hippocampal Neurogenesis in Adult Humans Cell, 153 (6), 1219-1227 DOI: 10.1016/j.cell.2013.05.002

van Praag, H. (2008). Neurogenesis and Exercise: Past and Future Directions NeuroMolecular Medicine, 10 (2), 128-140 DOI: 10.1007/s12017-008-8028-z

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Walking: the Cheap, Easy Workout

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Donated Blood Won't Transmit Alzheimer's, Parkinson's Disease

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Ketamine – More Than a Recreational Drug

Ketamine was first introduced in 1962. It was initially presented as a fast acting general anesthetic, being widely used as a battlefield anesthetic in the 1970s. Ketamine is considered a dissociative anesthetic – it creates an altered state of consciousness, distorting the perception of sound and vision, and producing a feeling of detachment from oneself and from the environment which provides pain relief, sedation, and amnesia.

In the clinic, ketamine is mainly used for starting and maintaining anesthesia. Given its fast sedative action, it is frequently used in emergency situations. Its main effects usually begin within five minutes of injection and last up to 25 minutes.

But ketamine can have some impactful psychological side-effects as the medication wears off, such as agitation, confusion, or hallucinations. The latter is the main reason for its use as a drug of abuse or recreational drug. Ketamine began to be illicitly consumed in the 1970s and, nowadays, it is equally known for its medical and recreational use. Ketamine can produce illusions or hallucinations that are enhanced by environmental stimuli, which explains its popularity as a club drug.

Ketamine is still used in medical contexts as an anesthetic, although its use has become less common and more restricted. However, in recent years, a new use for ketamine has been emerging.

Ketamine as an antidepressant drug

Recent studies have shown that ketamine has fast antidepressant actions in patients with major depressive disorder, even in those with the most treatment-resistant forms of depression. Major depressive disorder is a highly disabling condition with limited treatment options that are often ineffective. The onset of depression is poorly understood but it is thought to derive from a combination of neurochemical factors and triggering life events, such as overwhelming stress. Potential neurochemical factors include defects in the major neurotransmitters of the central nervous system, glutamate and GABA.

Glutamate is the major excitatory neurotransmitter in the central nervous system. Experimental studies in animal models of depression have associated glutamate with depression, showing that there may be altered levels of glutamate receptors; increased glutamate concentrations have also been found in the brains of patients with major depressive disorder. Since ketamine acts by blocking the action of the NMDA glutamate receptors, this is a likely mechanism for its fast action in depression.

Indeed, a single dose of ketamine has been shown to be able to normalize the activity of glutamate receptors. Importantly, the effects of ketamine occurred only at low doses, indicating that these antidepressant effects can occur without the psychological side effects associated with high doses of ketamine.

GABA, on the other hand, is the major inhibitory neurotransmitter in the central nervous system. It has also been associated with depression – mice with an impairment of GABAergic transmission exhibit behavioral signs that mimic the emotional patterns of depression, which supports the view of a causal link between GABAergic neurotransmission and depression. Major depressive disorder has been linked to reduced levels of GABA and GABA receptors, and to reduced expression of glutamic acid decarboxylase, an enzyme that converts glutamate to GABA.

These two effects may seem contradictory, but these deficits in the GABAergic system may actually lead to increased glutamate concentrations. However, some studies have also reported reduced rather than increased brain levels of glutamate. This has led to the hypothesis that depression may actually be associated with a dynamic balance between changes in GABAergic and glutamatergic transmission. The mechanisms underlying this possible relationship were mostly unknown, but a new study published on the journal Biological Psychiatry sheds light on this subject.

A matter of balance

A stable and regular functioning of neural networks relies on an ability to maintain a balance between inhibitory and excitatory neurotransmission. In the mentioned study, and with the goal of understanding how the balance between GABA and glutamate levels may be linked to depression, the consequences of GABAergic deficits on glutamatergic synapses were investigated. It was found that mice with depression associated with GABAergic deficits also showed reduced expression and function of glutamate receptors.

A decrease in the number and activity of glutamatergic synapses was also found. Treatment with a sub-anesthetic dose of ketamine led to a lasting normalization of glutamate receptor levels and glutamatergic synapse function. These results indicate that depression in mice with impaired GABAergic neurotransmission involves a balancing reduction of glutamatergic transmission that can be normalized for a prolonged period of time by the rapidly acting antidepressant ketamine.

This study thereby establishes the link between the GABAergic and glutamatergic deficits described for depression, and suggests that it may be caused by a dysregulation of the equilibrium mechanisms that act to restore the balance of excitation and inhibition. It is possible that conditions of chronic or repeated stress, which may trigger the development of depression, may do so by affecting the balance between GABA and glutamate levels, or by impairing the mechanisms that could restore that balance. Indeed, chronic stress has been shown to decrease the production of glutamate receptors and to render GABAergic inhibition ineffective.

This work also reinforced the antidepressant efficacy of ketamine. However, ketamine will always have a huge drawback due to its drug-of-abuse properties. The use of other NMDA glutamate receptor antagonists without the side-effects of ketamine has been tested with promising results, leading to similar effects as those obtained with ketamine. Here may lay the answer.

References

Garcia, L., Comim, C., Valvassori, S., Réus, G., Stertz, L., Kapczinski, F., Gavioli, E., & Quevedo, J. (2009). Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33 (3), 450-455 DOI: 10.1016/j.pnpbp.2009.01.004

Hashimoto, K., Sawa, A., & Iyo, M. (2007). Increased Levels of Glutamate in Brains from Patients with Mood Disorders Biological Psychiatry, 62 (11), 1310-1316 DOI: 10.1016/j.biopsych.2007.03.017

Ionescu, D., Luckenbaugh, D., Niciu, M., Richards, E., Slonena, E., Vande Voort, J., Brutsche, N., & Zarate, C. (2014). Effect of Baseline Anxious Depression on Initial and Sustained Antidepressant Response to Ketamine The Journal of Clinical Psychiatry, 75 (09) DOI: 10.4088/JCP.14m09049

Jansen, K. (2011). A Review of the Nonmedical Use of Ketamine: Use, Users and Consequences Journal of Psychoactive Drugs, 32 (4), 419-433 DOI: 10.1080/02791072.2000.10400244

Li, N., Lee, B., Liu, R., Banasr, M., Dwyer, J., Iwata, M., Li, X., Aghajanian, G., & Duman, R. (2010). mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science, 329 (5994), 959-964 DOI: 10.1126/science.1190287

Luscher, B., Shen, Q., & Sahir, N. (2010). The GABAergic deficit hypothesis of major depressive disorder Molecular Psychiatry, 16 (4), 383-406 DOI: 10.1038/mp.2010.120

Morgan, C., Curran, H., & , . (2012). Ketamine use: a review Addiction, 107 (1), 27-38 DOI: 10.1111/j.1360-0443.2011.03576.x

Niciu, M., Ionescu, D., Richards, E., & Zarate, C. (2013). Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder Journal of Neural Transmission, 121 (8), 907-924 DOI: 10.1007/s00702-013-1130-x

Ren, Z., Pribiag, H., Jefferson, S., Shorey, M., Fuchs, T., Stellwagen, D., & Luscher, B. (2016). Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine Treatment Biological Psychiatry DOI: 10.1016/j.biopsych.2016.02.009

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A Wimbledon win may be down to pumping iron in the gym, according to researchers who say the most successful elite male players of modern times are more muscular. via BBC News - Health Read More Here..

Playing card games aids stroke recovery

Playing simple card games, such as snap, can help stroke patients with their recovery, research suggests. via BBC News - Health Read More Here..

Huge newfound deposit of helium will keep MRI scanners running

Helium prospectors have uncovered a massive source of the vanishing gas, vital for MRI scanners, the Large Hadron Collider, NASA rocket fuel… and balloons via New Scientist - Health Read More Here..

Rio 2016 boss: Zika 'blown out of proportion'

The CEO of the 2016 Olympics has addressed concerns about Zika, the economy and the impact of the games on Brazil. via BBC News - Health Read More Here..

Supreme Court strikes down abortion restrictions in Texas

In a major victory for pro-choice advocates, the US Supreme Court struck down a Texas abortion law today via New Scientist - Health Read More Here..

Orlando medic: 'I can still see victims’ faces'

A doctor who treated victims of the Orlando massacre talks of the mental scars left by what he experienced. via BBC News - Health Read More Here..

Five New Genes Linked to Colon Cancer

But researchers say it's likely that all the major genetic mutations have been discovered

Source: HealthDay
Related MedlinePlus Pages: Colorectal Cancer, Genes and Gene Therapy via MedlinePlus Health News Read More Here..

Flint's Lead-Contamination Crisis 'Entirely Preventable'

CDC looks at kids' blood levels before, during and after city's switch to local water
Source: HealthDay
Related MedlinePlus Pages: Environmental Health, Lead Poisoning via MedlinePlus Health News Read More Here..

Hovering Parents May Harm Kids

Study found too much pressure for good grades raised risk for anxiety, depression

Source: HealthDay
Related MedlinePlus Pages: Child Mental Health, Parenting via MedlinePlus Health News Read More Here..

Drones Could Deliver Vaccines in Developing Countries

Machines might be cheaper, quicker than current delivery methods, study suggests

Source: HealthDay
Related MedlinePlus Pages: Immunization, International Health, Rural Health Concerns via MedlinePlus Health News Read More Here..