minocycline and Brain-Diseases

All pre-term newborns and a high proportion of term newborns develop neonatal jaundice. Neonatal jaundice is usually a benign condition and self-resolves within few days after birth. However, a combination of unfavorable complications may lead to acute hyperbilirubinemia. Excessive hyperbilirubinemia may be toxic for the developing nervous system leading to severe neurological damage and death by kernicterus. Survivors show irreversible neurological deficits such as motor, sensitive and cognitive abnormalities. Current therapies rely on the use of phototherapy and, in unresponsive cases, exchange transfusion, which is performed only in specialized centers. During bilirubin-induced neurotoxicity different molecular pathways are activated, ranging from oxidative stress to endoplasmic reticulum (ER) stress response and inflammation, but the contribution of each pathway in the development of the disease still requires further investigation. Thus, to increase our understanding of the pathophysiology of bilirubin neurotoxicity, encephalopathy and kernicterus, we pharmacologically modulated neurodegeneration and neuroinflammation in a lethal mouse model of neonatal hyperbilirubinemia. Treatment of mutant mice with minocycline, a second-generation tetracycline with anti-inflammatory and neuroprotective properties, resulted in a dose-dependent rescue of lethality, due to reduction of neurodegeneration and neuroinflammation, without affecting plasma bilirubin levels. In particular, rescued mice showed normal motor-coordination capabilities and behavior, as determined by the accelerating rotarod and open field tests, respectively. From the molecular point of view, rescued mice showed a dose-dependent reduction in apoptosis of cerebellar neurons and improvement of dendritic arborization of Purkinje cells. Moreover, we observed a decrease of bilirubin-induced M1 microglia activation at the sites of damage with a reduction in oxidative and ER stress markers in these cells. Collectively, these data indicate that neurodegeneration and neuro-inflammation are key factors of bilirubin-induced neonatal lethality and neuro-behavioral abnormalities. We propose that the application of pharmacological treatments having anti-inflammatory and neuroprotective effects, to be used in combination with the current treatments, may significantly improve the management of acute neonatal hyperbilirubinemia, protecting from bilirubin-induced neurological damage and death.

Topics: Animals; Animals, Newborn; Bilirubin; Brain Diseases; Disease Models, Animal; Hyperbilirubinemia, Neonatal; Inflammation; Kernicterus; Mice; Minocycline; Neuroimmunomodulation; Neuroprotective Agents; Neurotoxicity Syndromes; Phototherapy

Sepsis-associated encephalopathy is a major complication during sepsis, and an effective treatment remains unknown. Although minocycline (MINO) has neuroprotective effects and is an attractive candidate for treating sepsis-associated encephalopathy, the effect of MINO on synaptic plasticity during sepsis is still unclear. In the present study, we investigated the effects of MINO on long-term potentiation (LTP) in the hippocampus in a cecal ligation and puncture (CLP) mouse model. We divided mice into four groups; sham + vehicle, sham + MINO (60 mg/kg, i.p. for 3 consecutive days before slice preparation), CLP + vehicle, and CLP + MINO. We tested LTP in the CA1 region of the hippocampus, using slices taken 24 h after surgery. Because MINO is also anti-inflammatory, LTP was analyzed following 30 min of IL-1 receptor antagonist (IL-1ra) perfusion. The endotoxin level in the blood was increased at 24 h after CLP operations regardless of MINO administrations, and LTP in the CLP + vehicle group mice was severely impaired (P < 0.05). High doses of MINO prevented the LTP impairment during sepsis in the CLP + MINO group. Interleukin (IL)-1ra administration ameliorated LTP impairment only in the CLP + vehicle group (P < 0.05); it had no additional effects on LTP in the CLP + MINO group. In conclusion, we have provided the first evidence that MINO prevents impaired LTP related to sepsis-induced encephalopathy in the mouse hippocampus, and that mechanisms associated with IL-1 receptor activity may be involved.

Topics: Animals; Brain Diseases; Hippocampus; Long-Term Potentiation; Male; Mice; Minocycline; Sepsis

Postoperative cognitive dysfunction (POCD) is reported to occur frequently after all types especially cardiac surgery in elderly patients. It can be short-term or long-term and some cases even develop into Alzheimer's disease (AD). Although multi-risk factors associated with POCD have been identified, the etiology and pathophysiological mechanisms of this surgical complication remain elusive. Therefore, developing strategies for preventing or treating POCD is still challenging. However, increasing evidence suggests that central and systemic inflammation triggered by surgery likely plays a fundamental role in POCD developing and progression. Minocycline, a tetracycline derivative with anti-inflammatory properties, has been shown to be effective in treating neuroinflammatory related conditions or neurodegenerative diseases such as AD, Parkinson's disease, Huntington's disease. Considering that inflammation may be a potential factor of POCD and minocycline is effective in improving cognitive dysfunction induced by inflammation, we hypothesize that minocycline may be useful to treat/prevent the POCD development after surgery in elderly patients.

Topics: Aged; Anti-Bacterial Agents; Anti-Inflammatory Agents; Brain Diseases; Cognition Disorders; Humans; Inflammation; Minocycline; Models, Theoretical; Neurodegenerative Diseases; Postoperative Complications; Sepsis; Tetracycline; Treatment Outcome

Our previous studies have shown that intracerebral administration of endotoxin, lipopolysaccharide (LPS), induces selective white matter injury and hypomyelination in the neonatal rat brain and that the LPS-induced brain injury is associated with activation of microglia. To test the hypothesis that inhibition of microglial activation may protect against LPS-induced white matter injury, we examined roles of minocycline, a putative suppressor of microglial activation, on LPS-induced brain injury in the neonatal rat. A stereotactic intracerebral injection of LPS (1 mg/kg) was performed in postnatal day 5 Sprague-Dawley rats and control rats were injected with sterile saline. Minocycline (45 mg/kg) was administered intraperitoneally 12 h before and immediately after LPS injection and then every 24 h for 3 days. Inflammatory responses, activation of microglia and brain injury were examined 1 and 3 days after LPS injection. LPS injection resulted in brain injury in selective brain areas, including bilateral ventricular enlargement, cell death at the sub- and periventricular areas, loss of O4+ and O1+ oligodendrocyte (OL) immunoreactivity and hypomyelination, as indicated by decreased myelin basic protein immunostaining, in the neonatal rat brain. Minocycline administration significantly attenuated LPS-induced brain injury in these rat brains. The protective effect of minocycline was associated with suppressed microglial activation as indicated by the decreased number of activated microglial cells following LPS stimulation and with consequently decreased elevation of interleukin 1beta and tumor necrosis factor-alpha concentrations induced by LPS and a reduced number of inducible nitric oxide synthase expressing cells. Protection of minocycline was also linked with the reduction in LPS-induced oxidative stress, as indicated by 4-hydroxynonenal positive OLs. The overall results suggest that reduction in microglial activation may protect the neonatal brain from LPS-induced white matter injury and inhibition of microglial activation might be an effective approach for the therapeutic treatment of infection-induced white matter injury.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Brain; Brain Diseases; Cerebral Ventricles; Enzyme-Linked Immunosorbent Assay; Female; Immunohistochemistry; Injections; Interleukin-1; Lipopolysaccharides; Macrophage Activation; Male; Microglia; Minocycline; Neuroprotective Agents; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

A 79-year-old man with myelodysplastic syndrome developed a right optic neuropathy with optic disc edema and intractable periocular pain, one month after undergoing removal of a gangrenous gallbladder. Although results of a temporal artery biopsy were negative, he was treated with prednisone for presumed temporal arteritis. Attempts at tapering the prednisone dose led to recurrence of periocular pain. On neuro-ophthalmologic evaluation six months after the prednisone treatment was begun, he had developed right fourth and sixth cranial nerve palsies, and magnetic resonance imaging demonstrated a right orbital apex mass. Trans-sphenoidal biopsy revealed Aspergillus fumigatus. During treatment of aspergillosis, the patient developed a left hemiparesis. Magnetic resonance imaging disclosed multiple ring-enhancing cerebral masses. Biopsy revealed Nocardia asteroides. The patient was successfully treated for both infections with recovery of neurologic function except for the right optic neuropathy. Although immunocompromised patients are known to be subject to multiple infections, this may be the first reported case of concurrent sino-orbital aspergillosis and cerebral nocardiosis.

Topics: Aged; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Aspergillosis; Brain Diseases; Fatal Outcome; Humans; Imipenem; Magnetic Resonance Imaging; Male; Minocycline; Nocardia Infections; Orbital Diseases; Paranasal Sinus Diseases

Topics: Bone Marrow Transplantation; Brain Diseases; Drug Therapy, Combination; Humans; Magnetic Resonance Imaging; Male; Meropenem; Middle Aged; Minocycline; Nocardia asteroides; Nocardia Infections; Thienamycins; Transplantation, Homologous; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

A mouse model of cerebral nocardiosis was used to determine relative antibiotic efficacy by reducing bacterial colony counts per gram of brain tissue. The antimicrobial agents employed were demonstrated in vitro to be inhibitory to most strains of Nocardia asteroides at very low concentrations. The agents used in this study were imipenem-cilastatin, amikacin, trimethoprim-sulfamethoxazole, and minocycline. Antibiotics were administered every 4 h for 72 h before animal sacrifice. Bacterial colony counts were assayed at various time points before the completion of therapy. Imipenem-cilastatin and amikacin were the most effective agents tested. Trimethoprim-sulfamethoxazole was less effective than imipenem and amikacin but more effective than minocycline. Minocycline did not eradicate intracerebral organisms and was similar to saline (control) in its effects.

Topics: Amikacin; Animals; Brain Diseases; Drug Combinations; Female; Imipenem; Kinetics; Mice; Minocycline; Nocardia asteroides; Nocardia Infections; Sulfamethoxazole; Tetracyclines; Thienamycins; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Currently preferred therapy for CNS Nocardia infection is high-dose sulfonamide coupled with surgical drainage. Neither of these could be used in our patient; this led to therapy with minocycline alone. Several months after completion of minocycline therapy, the patient apparently is cured. His favorable outcome probably resulted from a combination of susceptibility of the organism to minocycline coupled with good CNS penetration of the agent resulting in CNS levels of drug 16 to 22 times higher than the Nocardia inhibitory concentration.

Topics: Alcoholism; Brain Diseases; Humans; Male; Middle Aged; Minocycline; Nocardia asteroides; Nocardia Infections; Tetracyclines

Topics: Brain; Brain Diseases; Brain Injuries; Holoprosencephaly; Humans; Minocycline; Water-Electrolyte Balance