Myoinositol in Neural tube Defects

Neural tube defects occur owing to the developmental issue related to spinal cord and brain. It is one of the most common among the congenital anomalies. Failure in the process of neural tube closure during the embryonic development often leads to severe birth defects that is termed as neural tube defects, including anencephaly and spina bifida. The patterns of inheritance of NTDs clearly indicates a major genetic contribution in the developing fetus however, while it is clearly established that non-genetic or environmental factors also play a key role in the development of NTDs¹.

It has been observed that some NTDs are not preventable by folic acid which leads to focus on  other nutritional factors that may contribute to prevention of NTDs. In this research study, A proportion of NTD cases can be prevented by peri-conceptional folic acid (FA) supplementation, as demonstrated in the 1991 Medical Research Council (MRC) Vitamin Study². However, NTD recurred in 1 % of pregnancies supplemented with 4 mg FA suggesting that some NTD cases are non-responsive to FA.

Fig 1 Neural Tube Defects³

Role of inositol in cellular functions and neural tube defects

Inositol (1,2,3,4,5,6-hexahydroxycyclohexane) is a naturally occurring simple six carbon sugar alcohol, sometimes

denoted as a pseudo-vitamin although it can be synthesized from glucose by means of conversion of glucose 6-phosphate to inositol 1-phosphate (Fig. 2). Plants, includinglegumes, oil seeds, and grains, are mostly rich in myo-inositol hexakisphosphate (IP₆; phytic acid). This molecule is mostly hydrolyzed to free inositol before absorption from the gut. The phosphoinositidesPI(3,4,5)P₃ andPI(4,5)P₂ are the major mediators in the signaling pathways that influence diverse cellular functions including preventing neural tube defects (Fig. 1).

Fig 2. Outline of pathways for synthesis of inositol phosphates and phosphoinositides.

There is much interest in the influence of inositol levels on NTD predisposition in which rat embryos were cultured in defined conditions through the period of neural tube closure. It has been observed that specific omission of several vitamins caused growth retardation or developmental abnormalities but NTDs occurred only in the absence of inositol. Similarly, deficiency of inositol in the culture medium causes cranial NTDs in mouse embryos, whereas deficiency of other vitamins, including folic acid, does not create such defects⁴.

Fig 3.Inositol concentration in the urine of the Prevention of Neural Tube Defects by Inositol on pilot study subjects.

In this study, inositol supplementation during pregnancy has proven to be safe for both mothers and babies in the randomised study group. This study provides an impetus to further evaluate inositol for primary prevention of NTD⁵.

Analysis of mice carrying gene-trap alleles that result in loss or diminished expression of inositol kinases suggests that both phosphoinositides and inositol polyphosphates play key cellular functions essential for neural tube closure. In particular, generation of higher inositol polyphosphates appears to be required during the stage of neural tube closure. Supplemental inositol could potentially act to overcome the underlying causative defect responsible for NTDs and/ or enhance the normal processes required for progression of neural tube closure.

References:

1. 1. Greene NDE, Copp AJ. 1997. Inositol prevents folate-resistant neural tube defects in the mouse. Nat Med 3:60–66.
   2. Medical Research Council Vitamin Study Research Group (1991) Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338, 131–137.
   3. Botto et al. Neural Tube Defects, N. Engl. J. Med. 1999;341:1509–19.
   4. Cockroft DL. 1979. Nutrient requirements of rat embryos undergoing organogenesis in vitro. J ReprodFertil 57:505-510.
   5. Nicholas D. E. Greene et al., Inositol for the prevention of neural tube defects: a pilot randomized controlled trial, British Journal of Nutrition (2016), 115, 974–983.
      

      Picture Credit: Familydoctor.org

Dr. Anju Parira [MBBS (Hons), MS (OB & Gyn)] Director & Consultant, MotherCare, Bokaro Steel City, Jharkhand.